Ventricular Stiffness Research Articles

Left Ventricular Stiffness in Adolescents and Young Adults After Arterial Switch Operation for Complete Transposition of the Great Arteries.

We tested the hypothesis that left ventricular (LV) myocardial stiffness is altered in patients with transposition of great arteries (TGA) after arterial switch operation (ASO) and explored its associations with myocardial calibrated integrated backscatter (cIB) and LV myocardial deformation. Thirty-one patients and twenty-two age-matched controls were studied. LV myocardial stiffness was assessed by diastolic wall strain (DWS) and stiffness indices including (E/e)/LV end-diastolic dimension, (E/LV global longitudinal early diastolic strain rate)/LV end-diastolic volume, and (E/LV global circumferential early diastolic strain rate)/LV end-diastolic volume, where E and e are early diastolic transmitral and mitral annular velocities, respectively. LV myocardial cIB and longitudinal and circumferential myocardial deformation were determined by conventional and speckle tracking echocardiography. Patients had significantly lower DWS, higher stiffness indices, and greater myocardial cIB than controls (all p < 0.05). The LV longitudinal and circumferential systolic strain and systolic and diastolic strain rates were significantly lower in patients than controls (all p < 0.05). Greater average myocardial cIB was associated with lower DWS (r = - 0.44, p = 0.002). Worse DWS and LV stiffness indices were found to correlate with lower mitral annular systolic velocity, mitral annular late diastolic velocity, and LV longitudinal late diastolic strain rate (all p < 0.05). LV longitudinal and circumferential systolic strain and strain rate were also found to correlate with DWS (all p < 0.05). In conclusion, LV myocardial stiffening occurs in adolescents and young adults with TGA after ASO and is associated with impairment of ventricular systolic and diastolic myocardial deformation and myocardial fibrosis.

Female Heart Health: Is GPER the Missing Link?

The G Protein-Coupled Estrogen Receptor (GPER) is a novel membrane-bound receptor that mediates non-genomic actions of the primary female sex hormone 17β-estradiol. Studies over the past two decades have elucidated the beneficial actions of this receptor in a number of cardiometabolic diseases. This review will focus specifically on the cardiac actions of GPER, since this receptor is expressed in cardiomyocytes as well as other cells within the heart and most likely contributes to estrogen-induced cardioprotection. Studies outlining the impact of GPER on diastolic function, mitochondrial function, left ventricular stiffness, calcium dynamics, cardiac inflammation, and aortic distensibility are discussed. In addition, recent data using genetic mouse models with global or cardiomyocyte-specific GPER gene deletion are highlighted. Since estrogen loss due to menopause in combination with chronological aging contributes to unique aspects of cardiac dysfunction in women, this receptor may provide novel therapeutic effects. While clinical studies are still required to fully understand the potential for pharmacological targeting of this receptor in postmenopausal women, this review will summarize the evidence gathered thus far on its likely beneficial effects.

Effects of Eplerenone on Blood Pressure and Echocardiographic and Serum Biochemical Variables in Five Healthy Dogs: A Pilot Study.

Eplerenone (EP), an aldosterone antagonist, is reported to produce renal and cardiac protective effects in noncanine species. However, there are no detailed reports available on cardiovascular effects of EP in dogs. This study aimed to determine effect of EP on echocardiographic parameters, blood pressures, and biochemical variables in healthy dogs. Five healthy Beagle dogs were randomly divided and repeatedly used in each of 3 dose groups, receiving 2.5, 5, or 10 mg/kg BW EP orally q24 h for 4 wks. Serum biochemical test, blood pressure, and Doppler echocardiography measurements were performed before EP administration and at 1, 2, and 4 weeks after EP administration. Treatment with EP reduced mean blood pressure in a dose-dependent manner and significantly (but in a dose-independent manner) decreased left atrium/aorta ratio, early diastolic transmitral flow, early diastolic transmitral flow/late diastolic transmitral flow, peak velocity of early diastolic transmitral flow/peak velocity of early diastolic mitral annular motion, left ventricle and right ventricle Tei indices, stroke volume, cardiac output, and mid systole myocardial velocity gradient 1 to 4 weeks after administration. Deceleration time of early diastolic transmitral flow significantly increased after EP administration. No significant changes were observed in serum biochemical variables. The results indicated that EP might reduce preload, thereby decreasing left atrial size. In addition, reduction of left ventricular stiffness may have theoretically taken place but this could not be tested using the present study design. It is suggested that EP administration within the dose range used in this study is safe for administration to healthy dogs. Further studies are needed to explore both safety and efficacy, as well as to seek a recommended dose range of EP treatment in client-owned dogs with heart disease.

Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone

ObjectivesThis study sought to assess if clinical phenogroups differ in comprehensive biomarker profiles, cardiac and arterial structure/function, and responses to spironolactone therapy. BackgroundPrevious studies identified distinct subgroups (phenogroups) of patients with heart failure with preserved ejection fraction (HFpEF). MethodsAmong TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) participants, we performed latent-class analysis to identify HFpEF phenogroups based on standard clinical features and assessed differences in multiple biomarkers measured from frozen plasma; cardiac and arterial structure/function measured with echocardiography and arterial tonometry; prognosis; and response to spironolactone. ResultsThree HFpEF phenogroups were identified. Phenogroup 1 (n = 1,214) exhibited younger age, higher prevalence of smoking, preserved functional class, and the least evidence of left ventricular (LV) hypertrophy and arterial stiffness. Phenogroup 2 (n = 1,329) was older, with normotrophic concentric LV remodeling, atrial fibrillation, left atrial enlargement, large-artery stiffening, and biomarkers of innate immunity and vascular calcification. Phenogroup 3 (n = 899) demonstrated more functional impairment, obesity, diabetes, chronic kidney disease, concentric LV hypertrophy, high renin, and biomarkers of tumor necrosis factor-alpha–mediated inflammation, liver fibrosis, and tissue remodeling. Compared with phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest (hazard ratio [HR]: 3.44; 95% confidence interval [CI]: 2.79 to 4.24); phenogroups 2 and 3 demonstrated similar all-cause mortality (phenotype 2 HR: 2.36; 95% CI: 1.89 to 2.95; phenotype 3 HR: 2.26, 95% CI: 1.77 to 2.87). Spironolactone randomized therapy was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 3 (HR: 0.75; 95% CI: 0.59 to 0.95; p for interaction = 0.016). Results were similar after excluding participants from Eastern Europe. ConclusionsWe identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. These findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF that may benefit from different targeted interventions.

Timing of Repair in Tetralogy of Fallot: Effects on Outcomes and Myocardial Health.

Early complete repair of tetralogy of Fallot (ToF) prior to 1 year of age has been demonstrated to be safe and has survival benefits over late repair. The age at repair of ToF affects long-term outcomes. This may largely be related to preserved, or comparatively better, myocardial health. Most studies advocate for an age of repair between 3 and 6 months and certainly below the age of 1 year. Patients with severe right ventricular outflow tract obstruction represent an exception to this rule and may require neonatal repair or surgical and catheter-based palliation before surgery. Older age at repair beyond the first birthday leads to unfavorable right ventricular remodeling with increased right ventricular stiffness and hypertrophy and is associated with increased long-term ventricular tachycardia and all-cause mortality. In this article, we review the short- and long-term benefits of early repair, with a focus on long-term morbidity. In conclusion, we emphasize the importance of myocardial health and the relationship to early repair and advocate for the use of magnetic resonance imaging in adult patients with repaired ToF to detect myocardial fibrosis.

Right ventricular myocardial stiffness and relaxation components by kinematic model-based analysis.

Right ventricle (RV) has frequently been described as the forgotten ventricle in the circulation. However, its importance in various cardiac diseases is now unquestioned. This recognition has led to improved risk stratification and development of algorithms for intervention, which incorporate measurements of RV function as key components of the assessment of many conditions. The diastolic function plays an important role in determining ventricular filling and stroke volume. Abnormal left ventricular (LV) diastolic function has been recognized in many cardiovascular diseases and is associated with worse outcomes, including total mortality and hospitalizations due to heart failure. In this review, we define what global RV diastolic function is, and how to measure it. This article indicates the validation of kinematic model parameters for assessing RV diastolic function. J. Med. Invest. 67 : 11-20, February, 2020.

Physiological and Metabolic Effects of Yellow Mangosteen (Garcinia dulcis) Rind in Rats with Diet-Induced Metabolic Syndrome.

Metabolic syndrome is a cluster of disorders that increase the risk of cardiovascular disease and diabetes. This study has investigated the responses to rind of yellow mangosteen (Garcinia dulcis), usually discarded as waste, in a rat model of human metabolic syndrome. The rind contains higher concentrations of phytochemicals (such as garcinol, morelloflavone and citric acid) than the pulp. Male Wistar rats aged 8–9 weeks were fed either corn starch diet or high-carbohydrate, high-fat diet for 16 weeks, which were supplemented with 5% freeze-dried G. dulcis fruit rind powder during the last 8 weeks. We characterised metabolic, cardiovascular, liver and gut microbiota parameters. High-carbohydrate, high-fat diet-fed rats developed abdominal obesity, hypertension, increased left ventricular diastolic stiffness, decreased glucose tolerance, fatty liver and reduced Bacteroidia with increased Clostridia in the colonic microbiota. G. dulcis fruit rind powder attenuated these changes, improved cardiovascular and liver structure and function, and attenuated changes in colonic microbiota. G. dulcis fruit rind powder may be effective in metabolic syndrome by appetite suppression, inhibition of inflammatory processes and increased fat metabolism, possibly related to changes in the colonic microbiota. Hence, we propose the use of G. dulcis fruit rind as a functional food to ameliorate symptoms of metabolic syndrome.

Statins with different lipophilic indices exert distinct effects on skeletal, cardiac and vascular smooth muscle

AimsData concerning the influence of statin lipophilicity on the myotoxic and pleiotropic effects of statins is conflicting, and mechanistic head-to-head comparison studies evaluating this parameter are limited. In order to address the disparity, this mechanistic investigation aimed to assess the effects of two short-acting statins with different lipophilic indices on skeletal, cardiac and vascular smooth muscle physiology. Materials and methodsYoung female Wistar rats were randomised to simvastatin (80 mg kg−1 day−1), pravastatin (160 mg kg−1 day−1) or control treatment groups. Changes in functional muscle performance were assessed, as well as mRNA levels of genes relating to atrophy, hypertrophy, mitochondrial function and/or oxidative stress. Key findingsThere were no significant differences in the mRNA profiles of isolated skeletal muscles amongst the treatment groups. In terms of skeleletal muscle performance, simvastatin reduced functionality but treatment with pravastatin significantly improved force production. Rodents given simvastatin demonstrated comparable myocardial integrity to the control group. Conversely, pravastatin reduced left ventricular action potential duration, diastolic stiffness and Mhc-β expression. Pravastatin improved endothelium-dependent relaxation, particularly in muscular arteries, but this effect was absent in the simvastatin-treated rats. The responsiveness of isolated blood vessels to noradrenaline also differed between the statin groups. The findings of this study support that the effects of statins on skeletal, cardiac and vascular smooth muscle vary with their lipophilic indices. SignificanceThe results of this work have important implications for elucidating the mechanisms responsible for the myotoxic and pleiotropic effects of statins.

Increased Myocardial Stiffness in Patients With High-Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B Heart Failure With Preserved Ejection Fraction.

Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high-risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated left ventricular (LV) myocardial stiffness in comparison with healthy controls as a key marker for future HFpEF. Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or troponin T [>0.6 pg/mL]) were recruited, along with 61 age- and sex-matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (eg, pulmonary capillary wedge pressure: LVH, 13.4±2.7 versus control, 11.7±1.7 mm Hg, P<0.0001). The LV was less distensible in LVH than in controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (pulmonary capillary wedge pressure - right atrial pressure), LV myocardial stiffness was nearly 30% greater in LVH than in controls (LVH stiffness constant, 0.053±0.027 versus controls, 0.042±0.020, P=0.028). LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than in age- and sex-matched controls and thus appears to represent a transitional state from a normal healthy heart to HFpEF. Although the LV myocardial stiffness of patients with LVH is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals. URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03476785 and NCT02039154.

Predictive value of left ventricular diastolic chamber stiffness in patients with severe aortic stenosis undergoing aortic valve replacement.

Despite improvements in cardiac haemodynamics and symptoms, long-term mortality remains increased in some patients after aortic valve replacement (AVR). Limited data exist on the prognostic role of left ventricular (LV) chamber stiffening in these patients. We performed a retrospective analysis in 1893 patients with severe aortic stenosis (AS) referred for AVR. LV end-diastolic pressure-volume relations (EDPVR, P = αV^β) were reconstructed from echocardiographic measurements of end-diastolic volumes and estimates of end-diastolic pressure (EDP). The impact of EDPVR-derived LV chamber stiffness (CS30, at 30 mmHg EDP) on all-cause mortality after AVR was evaluated. Mean age was 76 ± 10 years, 39% were females, and ejection fraction (EF) was 61 ± 12%. The mean LV chamber stiffness (CS30) was 2.2 ± 1.3 mmHg/mL. A total of 877 (46%) patients had high LV stiffness (CS30 >2 mmHg/mL). In these patients, the EDPVR curves were steeper and shifted leftwards, indicating higher stiffness at all pressure levels. These patients were slightly older, more often female, and had more prevalent comorbidities compared to patients with low stiffness. At follow-up [median 4.2 (interquartile range 2.8-6.3) years; 675 deaths], a higher CS30 was associated with lower survival (hazard ratio: 2.7 for severe vs. mild LV stiffening; P < 0.0001), both in patients with normal or reduced EF. At multivariate analysis, CS30 remained an independent predictor, even after adjusting for age, sex, comorbidities, EF, LV remodelling, and diastolic dysfunction. Higher preoperative LV chamber stiffening in patients with severe AS is associated with poorer outcome despite successful AVR.

Seipin Knockout Mice Develop Heart Failure With Preserved Ejection Fraction

The lean diabetic patients with heart failure with preserved ejection fraction (HFpEF) in Asia suffer from adverse clinical outcomes and poor life quality. The suitable animal models are urgently needed for mechanistic study and therapeutic innovations. Our study reports that lipodystrophic mice with seipin depletion are lean, diabetic, and recapitulate major manifestations of clinical HFpEF, thereby clarifying that lean diabetes per se may produce HFpEF characteristics. We further demonstrate that increased cardiac titin phosphorylation and reactive interstitial fibrosis associated with neutrophil extracellular traps lead to left ventricular stiffness and suggest that both pathways may be potential therapeutic targets in Asian HFpEF patients.

Pelargonidin 3-glucoside-enriched strawberry attenuates symptoms of DSS-induced inflammatory bowel disease and diet-induced metabolic syndrome in rats.

To determine whether the anthocyanin, pelargonidin 3-glucoside (P3G), attenuates symptoms of inflammatory bowel disease (IBD) and metabolic syndrome in rats. We tested P3G-enriched strawberry in two models of chronic inflammation in rats, chronic IBD induced by 0.5% dextran sodium sulphate in the drinking water for 12weeks (D) and metabolic syndrome induced by a high-carbohydrate, high-fat diet (H) for 16weeks. P3G-enriched strawberry was added to the diet for the final 6weeks in IBD rats (DP) or 8weeks in H rats (HP) to provide a dose of 8mg P3G/kg/day. D rats had marked diarrhoea, bloody stools, erosion of mucosal epithelium, crypt atrophy, loss of villi and goblet cells, and inflammatory cell infiltration. These symptoms were reversed by P3G with healthy stools and mucosal lining of ileum and colon including increased villi, crypts and goblet cells and reduced inflammation. H rats developed hypertension, dyslipidaemia, central obesity, increased ventricular stiffness, cardiac and liver inflammation, and steatosis. P3G treatment in H rats improved systolic blood pressure, ventricular stiffness, and cardiac and liver structure, and reduced abdominal fat, abdominal circumference and body weight gain. Our study indicates that dietary P3G decreased inflammation to decrease the symptoms of IBD, and to improve cardiovascular, liver and metabolic functions in metabolic syndrome.

Modulation of left ventricular diastolic filling during exercise in persons with cervical motor incomplete spinal cord injury.

To characterize left ventricular diastolic function during an exertional challenge in adults with incomplete cervical spinal cord Injury (icSCI). In this cross-sectional study, a two-group convenience sample was used to compare left ventricular LV diastolic performance during a 5-10 W·min-1 incremental arm ergometer exercise protocol, using bioimpedance cardiography. Subjects were eight males with cervical incomplete spinal cord injury (icSCI; C5-C7: age 39 ± 14 years) versus eight able-bodied males (CON: age 38 ± 13 years). Left ventricular (LV) diastolic indices included end-diastolic volume (EDV) and early diastolic filling ratio (EDFR). LV ejection time (LVET), inotropic index (dZ/dT2) and stroke volume (SV) were compared between the groups at peak exercise, and maximum workload for the icSCI group (isomax). EDV (at peak exercise:131.4 ± 7.3 vs 188.78 ± 9.4, p < 0.001; at isomax: 131.4 ± 7.3 vs 169 ± 23, p = 0.0009) and EDFR (at peak exercise 73 ± 14% vs 119 ± 11%, p = 0.006; at isomax 94 ± 10; p = 0.009) were significantly reduced in icSCI compared to CON, respectively. Significant differences in LVET (icSCI: 273 ± 48 vs CON: 305 ± 68; p = 0.1) and dZ/dT2 (icSCI: 0.64 ± 0.11 vs CON: 0.85 ± 0.31; p = 0.1) were not observed at isomax, despite a significant decrease in SV in the subjects with icSCI (77.1 ± 6.05mL vs 105.8 ± 9.2mL, p < 0.00) CONCLUSION: Left ventricular filling was impaired in the subjects with icSCI as evidenced at both peak exercise and isomax. It is likely that restrictions on the skeletal muscle pump mechanized the impairment but increased left ventricular wall stiffness could not be excluded as a mediator.

P3790Left ventricular stiffness assessed by diastolic wall strain predicts infrequent atrial fibrillation

Abstract Background Left ventricular (LV) stiffness as the passive LV filling property in the LV diastolic function has been reported to be related with the prevalence of atrial fibrillation (AF). On the other hand, a novel insertable monitoring (ICM) system is a powerful tool to detect AF with rare appearance in patients with embolic stroke of undetermined source (ESUS). We investigated whether the LV stiffness assessed by diastolic wall strain (DWS) predicts infrequent atrial fibrillation. Methods Fifty-five patients (41 males, 68±14 years) who underwent ICM implantation for ESUS (n=19) or unexplained syncope (n=36) were studied. DWS, left atrial (LA) stiffness and other measurements were assessed using transthoracic echocardiography before the ICM implantation. DWS was calculated from the M-mode echocardiographic measurement of the LV posterior wall thickness at end-systole (PWs) and end-diastole (PWd) during sinus rhythm, and DWS was defined as PWd/PWs. LA stiffness index was defined as the ratio of E/e' to LA peak strain. Results AF was detected in 20 patients (36%) during the follow-up periods (280±243 days). Patients with AF showed reduced DWS (0.30±0.07 vs. 0.41±0.08, p&lt;0.0001), larger LA volume index (39.0±10.9 vs. 32.3±9.0, p=0.0174), and higher age (74.6±10.4 vs. 64.6±14.9, p=0.0105). On the other hand, LA stiffness index, LA function (reservoir, booster, and conduit function estimated by LA volume), and LV relaxation function (E wave, E/A ratio, deceleration time) were not associated with detection of AF. There was no difference on AF detection rate between ESUS and unexplained syncope (26% vs. 42%, p=0.2604). On multivariate analysis, DWS was only independently associated with detection of AF (p&lt;0.0001, OR 5.647 for each 0.1 decrease in DWS, 95% CI 1.084–1.338). Moreover, patients with reduced DWS (&lt;0.38) had a higher risk of incidences of AF than patients with preserved DWS (figure). Figure 1 Conclusions LV stiffness assessed by DWS predicts infrequent AF. Reduced LV stiffness rather than LA dysfunction or LV relaxation dysfunction may be the main cause of AF in the early stages.

P611Relation of exercise intolerance and left ventricular diastolic function to myocardial fibrosis in the patients with hypertrophic cardiomyopathy

Abstract Myocardial fibrosis happened to increased left ventricular (LV) stiffness and higher LV filling pressure likewise diastolic dysfunction, as associated with clinical outcomes in patients with hypertrophic cardiomyopathy (HCMP). Additionally, reduced exercise capacity affected patients along a broad spectrum of clinical severity. The aim of study was to determine the relation between exercise intolerance and LV diastolic parameters to myocardial fibrosis in the patients with HCMP. We enrolled 289 patients with HCMP and normal LV systolic function (ejection fraction &gt;50%). Study populations underwent both cardiopulmonary exercise test (CPET) as estimating peak oxygen consumption (peak VO2) and cardiac magnetic resonance (CMR) as myocardial fibrosis by late gadolinium delayed enhancement (LGE). NT-proBNP levels were determined at baseline. Basic echocardiography was used to measure the diastolic parameters. The study population was included with 248 males (85.8%), and the median age of population was 53 years [interquartile range (IQR) 46–60]. Median follow-up was 6.5 years (IQR 3.2–8.6). The median value of Peak VO2 as a representation of exercise tolerance was 29.0 ml/kg/min (IQR 25.0–34.0) in study population. The amount of LGE on CMR was 14.27 mL (IQR 6.30–27.76). The median value of diastolic parameters as left atrium volume index (LAVI) and E/e' ratio, respectively, were 39.10 mL/m2 (IQR 31.30–47.25) and 10.88 (IQR 8.58–13.31). The median NT-proBNP level was 295.40pg/mL (IQR 139.10–687.70). After adjusting for age and gender, peak VO2 was inversely correlated with NT-proBNP (r=−0.274, p&lt;0.001). A linear regression analysis with adjusting age and gender showed that LAVI and E/e' as diastolic parameters could predict the peak VO2 (LAVI: β=−0.082, p&lt;0.001, E/e': β=−0.373, p&lt;0.001) and NT-proBNP (LAVI: β=11.454, p&lt;0.001, E/e': β=55.533, p&lt;0.001), as well as the LGE also could associate the peak VO2 (LGE: β=−0.075, p&lt;0.001) and NT-proBNP (LGE: β=16.194, p&lt;0.001). In conclusion, through the correlation among exercise tolerance, parameters of diastolic dysfunction, and myocardial fibrosis, we demonstrated that exercise intolerance and parameters of diastolic dysfunction could predict the myocardial fibrosis in patients with HCMP. We inferred the adverse effects of myocardial fibrosis, as assessed by LGE, lead to diastolic dysfunction and reduced the exercise tolerance. Acknowledgement/Funding None

P303Prognostic value of diastolic wall strain in patients with asymptomatic severe aortic stenosis

Abstract Background Diastolic wall strain (DWS) has been reported to be associated with left ventricular (LV) stiffness and worse clinical outcomes. We sought to assess the utility of this new index for prediction of prognosis in asymptomatic patients with severe aortic stenosis (AS). Methods Asymptomatic severe AS patients [peak flow velocity (PFV) ≥4.0m/s, mean pressure gradient (mPG) ≥40mmHg, aortic valve area (AVA) ≤1.0cm2, or indexed AVA ≤0.6cm2/m2)] diagnosed between July 2007 and April 2016 were included in this study. Patients with significant mitral valve disease, posterior wall motion abnormality, prior cardiac surgery, hypertrophic cardiomyopathy, and LV ejection fraction &lt;50% were excluded. DWS was calculated with a validated formula [DWS = (posterior wall thickness at end-systole − posterior wall thickness at end-diastole)/posterior wall thickness at end-systole]. All study patients were prospectively followed up to last visit or death until November 2017, and predictive value of all-cause death was assessed using Cox-proportional hazards modeling. Patients who underwent aortic valve replacement (AVR) during the study period were censored on the date of surgery. Results A total of 184 asymptomatic severe AS, 138 (age 76±9year-old, men 41%, PFV 3.9±1.0m/s, mPG 38±19mmHg, AVA 0.83±0.18cm2, indexed AVA 0.56±0.13cm2/m2) met all study criteria. Of whom, 43 (31%) underwent AVR and 28 (20%) died during a mean follow-up of 25±28months. In a multivariable model after adjusting for clinical and echocardiographic variables, advancing age (per10yrs; HR=2.19, 95% CI=1.19–4.03, P&lt;0.05), history of hemodialysis (HR=4.31, 95% CI=1.30–14.35, P&lt;0.05), and low-DWS (DWS &lt;0.30) (HR=2.83, 95% CI=1.25–6.40, P&lt;0.05) were independent predictors of all-cause death. In the Kaplan-Meier estimates of cumulative survival stratified by DWS status were shown (Figure). The Kaplan-Meier estimates of survival Conclusion Low-DWS provides prognostic information in patients with asymptomatic severe AS.

P4351Validation by cardiac catheterization of noninvasive evaluation of left ventricular chamber and myocardial stiffness as a diastolic function using speckle tracking echocardiography

Abstract Background Left ventricular (LV) diastolic function is mainly composed of LV relaxation and LV stiffness. We reported that pulmonary capillary wedge pressure (ePCWP) and LV relaxation assessed by Tau (eTau) are noninvasively evaluated by speckle tracking echocardiography (STE). The minimum LV diastolic pressure (mLVP) was reported to have a strong correlation with Tau. Therefore, LV chamber stiffness (c-stiffness) may be assessed with the use of two LV diastolic pressure-volume coordinates: the mLVP and volume and the end-diastolic pressure (EDP) and volume. Purpose We sought to noninvasively assess LV stiffness using STE and validate the value by cardiac catheterization. Methods Echocardiography and catheterization were performed in 124 patients (age 72±8) (70 angina pectoris, 20 prior myocardial infarction, 19 hypertensive heart disease, 11 congestive heart failure and 4 paroxysmal atrial fibrillation). The ePCWP (mmHg) is noninvasively obtained as 10.8 − 12.4 × Log (left atrial active emptying function/minimum volume) and the eTau (ms) is obtained as isovolumic relaxation time/(ln 0.9 × systolic blood pressure − ln ePCWP) as previously reported. The mLVP (e-mLVP) was estimate using Tau. The estimated EDP (e-EDP) was calculated as 12.3 − 10.1 × Log (left atrial active emptying function / minimum volume). LV c-stiffness (mmHg/ml) was calculated as LV pressure change (from mLVP to EDP) obtained by catheterization divided by LV volume change during diastole which equals to stroke volume by echocardiography. Estimated c-stiffness (e-c-stiffness) was noninvasively obtained using e-mLVP and e-EDP. Furthermore, LV myocardial stiffness (m-stiffness) was calculated by LVED stress / LV longitudinal strain by STE, where LV stress (kdynes/cm2) was calculated as 0.334 × pressure × dimension / [thickness (1 + thickness/dimension)]. The estimated m-stiffness (e-m-stiffness) was calculated using e-EDP. Results The eTau and e-EDP estimated by STE had a good correlation with Tau and EDP invasively obtained by catheterization (r=0.75 and 0.63, respectively, both p&lt;0.001). There was a good correlation between Tau and mLVP (Tau = 2.06 mLVP + 33.7, r=0.70). The estimated LVED stress had good correlation with ED stress obtained by catheterization (r=0.77, p&lt;0.001). The e-c-stiffness and e-m-stiffness had a good correlation with those obtained by catheterization (e-c-stiffness; 0.116±0.07 and c-stiffness; 0.115±0.06, r=0.603, e-m-stiffness; 0.81±0.41 and m-stiffness; 0.85±0.45, r=0.89, respectively). Bland-Altman analysis revealed a good agreement between e-c-stiffness and c-stiffness, and between e-m-stiffness and m-stiffness without fixed and proportional bias. Conclusion This study demonstrated that LV stiffness may be noninvasively assessed by STE with reasonable accuracy and may have utility and value in the routine clinical practice for the diagnosis and treatment in patients with diastolic dysfunction.

P2258Pulse wave velocity, total arterial compliance, and cardiac structure and function in late life

Abstract Background Coupled abnormalities in arterial and left ventricular (LV) stiffness characterize aging and heart failure with preserved ejection fraction. We hypothesized that two measures of aortic stiffness, pulse wave velocity (PWV; reflecting segmental arterial wall stress in late systole) and total arterial compliance (TAC; reflecting distensibility of entire arterial system) differentially relate to cardiac structure and function in the elderly. Methods Among participants in the Atherosclerosis Risk In Community (ARIC) study, we assessed the cross-sectional relationship of carotid-femoral PWV (cfPWV) and TAC with echocardiographic measures of cardiac structure and function using multivariable linear regression adjusting for demographics and co-morbidities. TAC defined as stroke volume over pulse pressure [mL/mmHg]. Exclusions were LVEF &lt;50%, prevalent HF, ≥moderate valvular disease. Results Of the 4,141 participants included in this study, mean age was 75±5 years, 41% were male, and 80% were white. Mean values were: cfPWV: 11.7±3.4 m/sec; TAC: 1.1±0.3 mL/mmHg. Greater cfPWV was associated with greater LV mass, worse systolic function, and worse diastolic function (Table). In contrast, worse TAC was not related to LV structure and did not demonstrate consistent relationships with measures of LV diastolic function, but was associated with worse LV longitudinal strain. Echo measures cfPWV (1SD increase) TAC (1SD decrease) β Coefficient p-value β Coefficient p-value Cardiac structure Mean wall thickness, cm 0.10 &lt;0.001 -0.01 0.499 LVMI, g/m2 0.04 0.016 0.02 0.299 LVEDVI, ml/m2 -0.07 &lt;0.001 -0.02 0.332 LV systolic function LVEF (Simpson's), % -0.04 0.01 -0.16 &lt;0.001 Longitudinal strain, % 0.14 &lt;0.001 0.19 &lt;0.001 LV diastolic function Septal e', cm/sec -0.08 &lt;0.001 -0.02 0.169 E/e' septal 0.04 0.005 -0.02 0.138 LAVI, ml/m2 -0.05 0.003 -0.04 0.026 Conclusion Two non-invasive measures of aortic stiffness, cfPWV and TAC, demonstrate differential associations with LV structure and function in late life. Greater cfPWV is more robustly associated with LV structure and function than TAC.

P5459Comparison of the predictive role of changes in left ventricular mass and arterial stiffness for coronary artery disease in essential hypertension: Data from a 8-year-follow-up study

Abstract Background/Introduction Although arterial stiffening is related to atherosclerosis progression, its prognostic role in hypertension is not fully elucidated, while augmented left ventricular mass index (LVMI) is linked to adverse outcome. Purpose The aim of the present study was to compare the predictive role of changes in arterial stiffness and LVMI for the incidence of coronary artery disease (CAD) in a cohort of essential hypertensive patients. Methods We followed up 1082 essential hypertensives (mean age 55.9 years, 562 males, office blood pressure (BP)=145/91 mmHg) free of cardiovascular disease for a mean period of 8 years. All subjects had at least one annual visit and at baseline and last visit underwent complete echocardiographic study for estimation of LVMI and measurements of arterial stiffness on the basis of carotid to femoral pulse wave velocity (PWV), by means of a computerized method. The distribution of PWV was split by the median (8.2 m/sec) and accordingly subjects were classified into those with high (n=546) and low values (n=536). Moreover, LV hypertrophy (LVH) was defined as LVMI ≥125 g/m2 in males and LVMI ≥110 g/m2 in females, while CAD was defined as the history of myocardial infarction or significant coronary artery stenosis revealed by angiography or coronary revascularization procedure. Results The incidence of CAD over the follow-up period was 3.5%. Hypertensives who developed CAD (n=38) compared to those without CAD at follow-up (n=1044) had at baseline higher waist circumference (101.7±10.1 vs 96.2±11.6 cm, p=0.004), LVMI (123.9±22.1 vs 105.8±21.3 g/m2, p=0.026), prevalence of LVH (46% vs 25%, p=0.018) and prevalence of high PWV levels (67% vs 40%, p=0.021). No difference was observed between hypertensives with CAD and those without CAD with respect to baseline office BP, serum creatinine and lipid levels (p=NS for all). By univariate Cox regression analysis, it was revealed that changes in PWV levels between baseline and last visit predicted CAD (hazard ratio=1.243, p=0.014). However, in multivariate Cox regression model baseline glomerular filtration rate (hazard ratio=1.029, p=0.015) and changes in LVMI (hazard ratio=1.036, p&lt;0.0001) but not alterations of PWV turned out to be independent predictors of CAD. Conclusions In essential hypertensive patients changes in LVMI predict future development of CAD, whereas PWV alterations exhibit no independent prognostic value. These findings support that LVMI constitutes a superior prognosticator of events than PWV and its estimation is essential in order to improve overall risk stratification in hypertension.

P1629Crispr/Cas9 to elucidate cardiac specific effects of Gdf11

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a prevalent clinical condition in the aging population. HFpEF lacks specific therapies with a significant impact on survival, different therapeutic approaches have indeed failed, indicating a specific need in understanding the pathophysiology of the disease. Cardiac hypertrophy is one of the main features of HFpEF that contributes to impair diastolic function. Reducing ventricular stiffness associated with cardiomyocyte hypertrophy may indeed result in improved diastolic filling. Growth differentiation factor 11 (Gdf11), a TGF-β family factor, has been identified as a circulating factor able to reduce cardiac hypertrophy. Purpose Similar to myostatin (Gdf8), Gdf11 promotes the activation of atrophy pathways that induce ubiquitination of sarcomeric proteins. Gdf11 and Gdf8 activate both type I and II Tgf-β receptors, specifically by interacting with Acvr2a and Acvr2b (type II) and Alk 4/5/7 (type I), they activate Smad 3/4 pathway. Our data indicate a specific and more potent effect of Gdf11 in reducing cardiomyocytes size that is not recapitulated by Gdf8. Understanding the specific effect of Gdf11 on cardiomyocytes is crucial to develop therapeutic strategies to target the hypertrophic phenotype. Methods To investigate the effects of specific type I receptor KO on Smad signaling cascade we performed our preliminary experiment on HL-1 cells, a cardiac muscle cell line carrying a doxycycline inducible Cas9 transgene. Cell sensitivity of HL-1 to Gdf11 and Gdf8 was tested by performing a dose-response curve using a luciferase reporter for Smad 3/4 pathway activation (CAGA12). Selective Tgf-β type I receptor KO was induced using, for each receptor, two sgRNAs that have been designed to cleave the receptor coding sequence creating INDEL mutations and disrupt proper translation of the protein and confirmed by western blotting. Smad 3/4 activity was measured using a CAGA12-luciferase assay on HL-1-Cas9 transduced cells. Results Our data in HL-1 cells confirm a more potent effect of Gdf11 in activating Smad 3/4 pathway when compared to Gdf8 (Fig. 1A). Selective Alk4 and Alk5 KO induced a similar reduction in Smad 3/4 activation for both Gdf11 and Gdf8. Interestingly, Alk7 KO significantly reduced Gdf11 signaling that was not recapitulated when using Gdf8, suggesting that Alk7 receptor is crucial for Gdf11-dependent Smad 3/4 activation in HL-1 cells (Fig. 1B). Figure 1 Conclusions Our preliminary results indicate that part of Gdf11 cardiac specificity when compared to Gdf8 may reside in the usage of Alk7 for signaling. Alk7 has proposed as a protective factor for pathological cardiac hypertrophy by negatively regulating Mek-Erk1/2 signalling. Our results are now under investigation in vitro using mouse neonatal cardiomyocytes expressing Cas-9 and in vivo using cardiac-specific-Cas9-expressing C57 transgenic mice, in resting condition and after induction of pathological hypertrophy.