Ischemic stroke and the emerging role of left atrial function.

INTRODUCTION: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Emerging evidence suggests that left atrial (LA) dysfunction could play a role in the pathophysiology of ischemic stroke, as a possible contributor and as a predictive biomarker. AREAS COVERED: This narrative review details the intricate relationship between LA function, atrial fibrillation (AF), and ischemic stroke. We discuss imaging techniques used to assess LA function, the mechanisms by which impaired LA function may contribute to stroke, and its potential as a prognostic marker of stroke. EXPERT OPINION: There is a lack of evidence-based treatments of LA dysfunction in both primary and secondary stroke prevention. This is partly due to the lack of a practical clinical definition and unanswered questions concerning the clinical implications of LA dysfunction in patients without AF. Until such questions are resolved, addressing well-known cardiovascular risk factors, like hypertension and obesity, should be prioritized for preventing AF and ischemic stroke. These risk factors are closely tied to atrial remodeling, emphasizing the importance of targeting primary modifiable factors for preventing future morbidity and mortality.

Myocardial work in chronic kidney disease: insights from the CPH-CKD ECHO Study.

BACKGROUND: Myocardial work is a novel echocardiographic measure that offers detailed insights into cardiac mechanics. We sought to characterize cardiac function by myocardial work in patients with chronic kidney disease (CKD). METHODS: We prospectively enrolled 757 patients with non-dialysis-dependent CKD and 174 age- and sex-matched controls. Echocardiographic pressure-strain loop analysis was performed to acquire the global work index (GWI). Linear regressions were performed to investigate the association between estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) to GWI. RESULTS: Patients with CKD had a mean age of 57 years, 61% were men, and median eGFR was 42 mL/min/1.73 m2. Overall, no difference in GWI was observed between patients and controls (1879 vs. 1943 mmHg%, p = 0.06). However, a stepwise decline in GWI was observed for controls vs. patients with CKD without left ventricular hypertrophy vs. patients with CKD and left ventricular hypertrophy (GWI, 1943 vs. 1887 vs. 1789 mmHg%; p for trend = 0.030). In patients with CKD, eGFR was not associated with GWI by linear regression. However, diabetes modified this association (p for interaction = 0.007), such that per 10 mL/min/1.73 m2 decrease in eGFR, GWI decreased by 22 (9-35) mmHg% (p = 0.001) after multivariable adjustments in patients without diabetes, but with no association between eGFR and GWI in patients with diabetes. No association was observed between UACR and GWI. CONCLUSION: Patients with CKD and left ventricular hypertrophy exhibited lower myocardial work compared to matched controls. Furthermore, decreasing eGFR was associated with decreasing myocardial work only in patients without diabetes. No association to UACR was observed.

The role of aetiology in cardiac manifestations of chronic kidney disease: the CPH-CKD ECHO study.

PURPOSE: We investigated the associations between cardiac parameters and aetiologies of CKD in an exploratory study. METHODS: The study population consisted of 883 participants, 174 controls and 709 patients with aetiologies of CKD including diabetic nephropathy/renovascular KD in diabetes mellitus, hypertensive/renovascular nephropathy, tubulointerstitial nephritis, glomerulonephritis/vasculitis, polycystic KD (PKD), and CKD of unknown origin. Echocardiographic measures included left ventricular (LV) ejection fraction, global longitudinal, area, and radial strain, E/e' ratio, and LV mass index. These were compared between each aetiological group and controls in unadjusted and adjusted analysis. RESULTS: In unadjusted analysis, patients with diabetic nephropathy/renovascular KD in diabetes mellitus, had impaired LV ejection fraction (Median [IQR]: 56% [49.9,60.69] vs. 60.8% [57.7,64.1]), global longitudinal (mean ± SD: 13.1 ± 3.5% vs. 15.5 ± 2.6%), area (24.1 ± 5.8% vs. 28.5 ± 4.2%), and radial strain (36.2 ± 11.2% vs. 44.1 ± 9.7%), and increased LV mass index (89.1 g/m2 [71.8,104.9] vs. 69,0 g/m2 [57.9,80.8]) and E/e' ratio (10.6 [8.5,12.6] vs. 7 [5.8,8.3], p < 0.001 for all) compared with controls. Associations were similar for CKD of unknown origin. Patients with hypertensive/renovascular nephropathy had impaired global longitudinal and area strain, and higher E/e' ratio. Patients with glomerulonephritis/vasculitis had higher LV mass index, while patients with PKD had better global longitudinal strain than controls. All findings remained significant in adjusted analysis, except for the impaired global longitudinal strain in hypertensive/renovascular nephropathy. CONCLUSION: Glomerulonephritis/vasculitis, hypertensive/renovascular nephropathy, CKD of unknown origin, and diabetic nephropathy/renovascular KD in diabetes mellitus were increasingly associated with adverse cardiac findings, while PKD and tubulointerstitial nephritis were not. Aetiology might play a role regarding the cardiac manifestations of CKD.

Left Atrial Strain Predicts Subclinical Atrial Fibrillation Detected by Long-term Continuous Monitoring in Elderly High-Risk Individuals.

BACKGROUND: Left atrial (LA) speckle tracking provides detailed information on atrial function. Its utility for predicting subclinical atrial fibrillation (SCAF) is unclear. Therefore, we sought to investigate whether LA strain measures could predict SCAF detected by long-term continuous rhythm monitoring. METHODS: This was an echocardiographic substudy of the LOOP study, where elderly at risk of stroke were randomized to receive a loop recorder (Reveal LINQ) or control. Participants who received a loop recorder were included in this analysis. Echocardiography included LA reservoir, conduit, and contraction strain. Participants were followed with continuous rhythm monitoring for SCAF (≥6 minutes). Cox proportional hazards regression was applied to adjust for atrial fibrillation risk factors. RESULTS: In total, 956 participants were eligible for analysis. Median continuous rhythm monitoring was 35 months (IQR, 20-40 months), during which 278 (29%) were diagnosed with SCAF. The mean age was 74 years, 56% were male, median CHA2DS2-VASc-score was 4. LA reservoir strain was an independent predictor of SCAF after multivariable adjustments (HR, 1.04 [1.02-1.05], per 1% decrease) and so was contraction strain. The findings were unchanged in competing risk analyses and in participants with normal LA size and diastolic function. Participants with low reservoir strain (<33%) had a significantly higher risk of SCAF compared with those with high reservoir strain (incidence rate, 14.5 [12.4-16.9] versus 9.8 [8.2-11.8] events/100 person-years). The same was noted for low versus high contraction strain. CONCLUSIONS: LA reservoir and contraction strain are independent predictors of SCAF in elderly at risk of stroke. This also applies to individuals with normal LA size and diastolic function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02036450.

The relationship between coronary artery calcium and layer-specific global longitudinal strain in patients with suspected coronary artery disease.

PURPOSE: Layer-specific global longitudinal strain (GLS) may provide important insights in patients with suspected coronary artery disease (CAD). We aimed to investigate the association between layer-specific GLS and coronary artery calcium score (CACS) in patients suspected of CAD. METHODS: We performed a retrospective study of patients suspected of CAD who underwent both an echocardiogram and cardiac computed tomography (median 42 days between). Layer-specific (endocardial-, whole-layer-, and epicardial-) GLS was measured using speckle tracking echocardiography. We assessed the continuous association between layer-specific GLS and CACS by negative binomial regression, and the association with high CACS (≥400) using logistic regression. RESULTS: Of the 496 patients included (mean age 59 years, 56% male), 64 (13%) had a high CACS. Those with high CACS had reduced GLS in all layers compared to those with CACS < 400 (endocardial GLS: -20.5 vs. -22.7%, whole-layer GLS: -17.7 vs. -19.4%, epicardial GLS: -15.3 vs. -16.9%, p < .001 for all). Negative binomial regression revealed a significant continuous association showing increasing CACS with worsening GLS in all layers, which remained significant after multivariable adjustment including SCORE chart risk factors. All layers of GLS were associated with high CACS in univariable analyses, which was consistent after multivariable adjustment (endocardial GLS: OR = 1.11 (1.03-1.20); whole-layer GLS: OR = 1.14 (1.04-1.24); epicardial GLS: OR = 1.16 (1.05-1.29), per 1% absolute decrease). CONCLUSION: In this study population with patients suspected of CAD and normal systolic function, impaired layer-specific GLS was continuously associated with increasing CACS, and decreasing GLS in all layers were associated with presence of high CACS.

Right Ventricular Function in Arrhythmogenic Right Ventricular Cardiomyopathy: Potential Value of Strain Echocardiography.

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy, characterized by abnormal cell adhesions, disrupted intercellular signaling, and fibrofatty replacement of the myocardium. These changes serve as a substrate for ventricular arrhythmias, placing patients at risk of sudden cardiac death, even in the early stages of the disease. Current echocardiographic criteria for diagnosing arrhythmogenic right ventricular cardiomyopathy lack sensitivity, but novel markers of cardiac deformation are not subject to the same technical limitations as current guideline-recommended measures. Measuring cardiac deformation using speckle tracking allows for meticulous quantification of global systolic function, regional function, and dyssynchronous contraction. Consequently, speckle tracking to quantify myocardial strain could potentially be useful in the diagnostic process for the determination of disease progression and to assist risk stratification for ventricular arrhythmias and sudden cardiac death. This narrative review provides an overview of the potential use of different myocardial right ventricular strain measures for characterizing right ventricular dysfunction in arrhythmogenic right ventricular cardiomyopathy and its utility in assessing the risk of ventricular arrhythmias.

Left atrial strain is associated with long-term mortality in acute coronary syndrome patients.

To investigate the long-term prognostic value of the left atrial (LA) strain indices - peak atrial longitudinal strain (PALS), peak conduit strain (PCS), and peak atrial contractile strain (PACS) in acute coronary syndrome (ACS) patients in relation to all-cause mortality. This retrospective study included ACS patients treated with percutaneous coronary intervention (PCI) and examined with echocardiography. Exclusion criteria were non-sinus rhythm during echocardiography, missing images, and inadequate image quality for 2D speckle tracking analysis of the LA. The endpoint was all-cause death. Multivariable Cox regression which included relevant clinical and echocardiographic measures was utilized to assess the relationship between LA strain parameters and all-cause mortality. A total of 371 were included. Mean age was 64 years and 76% were male. Median time to echocardiography was 2 days following PCI. During a median follow-up of 5.7 years, 83 (22.4%) patients died. Following multivariable analysis, PALS (HR 1.04, 1.01-1.06, p = 0.002, per 1% decrease) and PCS (HR 1.05, 1.01-1.09, p = 0.006, per 1% decrease) remained significantly associated with all-cause mortality. PALS and PCS showed a linear relationship with the outcome whereas PACS was associated with the outcome in a non-linear fashion such that the risk of death increased when PACS < 18.22%. All LA strain parameters remained associated with worse survival rate when restricting analysis to patients with left atrial volume index < 34 ml/m2. Reduced LA function as assessed by PALS, PCS, and PACS were associated with an increased risk of long-term mortality in patients with ACS.

Normal values for left atrial strain, volume, and function derived from 3D echocardiography: the Copenhagen City Heart Study.

AIMS: 3D echocardiographic (3DE) assessment of the left atrium (LA) is a new modality of potential clinical value. Age- and sex-based normative values are needed to benchmark these parameters for clinical use. METHODS AND RESULTS: Of 4466 participants in the 5th Copenhagen City Heart Study, a prospective longitudinal cohort study on the general population, 2082 participants underwent 3DE of the LA. Healthy participants were included to establish normative values for LA strain, volume, and function by 3DE. The effects of age and sex were also evaluated. After excluding participants with comorbidities, 979 healthy participants (median age 44 years, 39.6% males) remained. The median and limits of normality (2.5th and 97.5th percentiles) for functional and volumetric measures were as follows: LA reservoir strain (LASr) 30.8% (18.4-44.2%), LA conduit strain (LAScd) 19.1% (6.8-32.0%), LA contractile strain 11.7% (4.3-22.2%), total LA emptying fraction (LAEF) 61.4% (47.8-71.0%), passive LAEF 37.7% (17.4-53.9%), active LAEF 37.4% (22.2-52.5%), LA minimum volume index (LAVimin) 10.2 (5.9-18.5) mL/m2, and LA maximum volume index (LAVimax) 26.8 (16.5-40.1) mL/m2. All parameters changed significantly with increasing age (P value for all <0.001). Significant sex-specific differences were observed for all parameters except active LAEF and LAVimax. Sex significantly modified the association between age and LASr (P for interaction < 0.001), LAScd (P for interaction < 0.001), LAVimin (P for interaction = 0.037), and total LAEF (P for interaction = 0.034) such that these parameters deteriorated faster with age in females than males. CONCLUSION: We present age- and sex-specific reference material including limits of normality for LA strain, volume, and function by 3DE.

Normal age- and sex-based values of right ventricular free wall and four-chamber longitudinal strain by speckle-tracking echocardiography: from the Copenhagen City heart study.

AIM: To promote the implementation of right ventricular (RV) longitudinal strain in clinical practice, we sought to propose normal values for RV free wall (RVFWLS) and four-chamber longitudinal strain (RV4CLS) and investigate the association with clinical and echocardiographic parameters in participants from the general population. METHODS AND RESULTS: Participants from the 5th Copenhagen City Heart Study (2011-2015)-a prospective cohort study-with available RV longitudinal strain measurements were included. RVFWLS and RV4CLS were assessed using two-dimensional speckle-tracking echocardiography. In total, 2951 participants were included. Amongst 1297 participants without cardiovascular disease or risk factors (median age 44, 63% female), mean values of RVFWLS and RV4CLS were - 26.7% ± 5.2 (95% prediction interval (PI) - 36.9, - 16.5) and - 21.7% ± 3.4 (95%PI - 28.4, - 15.0), respectively. Women had significantly higher absolute values of RVFWLS and RV4CLS than men (mean - 27.5 ± 5.5 vs. - 25.4 ± 4.5, p < 0.001 and - 22.3 ± 3.5 vs. - 20.6 ± 3.0, p < 0.001, respectively). Absolute values of RVFWLS but not RV4CLS decreased significantly with increasing age in unadjusted linear regression. Tricuspid annular plane systolic excursion, RV s' and left ventricular global longitudinal strain were the most influential parameters associated with both RVFWLS and RV4CLS in multiple linear regression. Participants with cardiovascular disease (n = 1531) had a higher proportion of abnormal values of RVFWLS and RV4CLS compared to the healthy population (8% vs. 4%, p < 0.001 and 8% vs. 3%, p < 0.001, respectively). CONCLUSION: This study proposed normal age- and sex-based values of RVFWLS and RV4CLS in a healthy population sample and showed significant sex differences in both measurements across ages.

Association between myocardial work indices and cardiovascular events according to hypertension in the general population.

AIMS: Pressure-strain loop (PSL) analysis is a novel echocardiographic tool capable of assessing myocardial work non-invasively. In this study, we aim to evaluate the prognostic value of myocardial work indices in the general population. METHODS AND RESULTS: This was a prospective community-based cohort study (n = 4466). PSL analyses were performed to acquire global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency (GWE). The endpoint was a composite of heart failure or cardiovascular death (HF/CVD). Survival analysis was applied. A total of 3932 participants were included in this analysis (median age: 58 years, 43% men). Of these, 124 (3%) experienced the outcome during a median follow-up period of 3.5 years [interquartile range (IQR): 2.6-4.4 years]. Hypertension significantly modified the association between all work indices and outcome (P for interaction < 0.05), such that work indices posed a higher risk of outcome in non-hypertensive than in hypertensive participants. After adjusting for Atherosclerosis Risk in Communities (ARIC)-HF risk variables, all work indices predicted outcome in non-hypertensive participants, but only GWI, GCW, and GWE predicted outcome in hypertensive participants [GWI: hazard ratio (HR) = 1.12 (1.07-1.16), per 100 mmHg% decrease; GCW: HR = 1.12 (1.08-1.17), per 100 mmHg% decrease; GWE: HR = 1.08 (1.04-1.12), per 1% decrease]. Only GWE significantly increased C-statistics when added to ARIC-HF risk variables in hypertensive participants (C-stat 0.865 vs. 0.877, P for increment = 0.003). CONCLUSION: Hypertension modifies the association between myocardial work indices and HF/CVD in the general population. All work indices are associated with outcome in normotensive participants. GWI, GCW, and GWE are independently associated with outcome in hypertension, but only GWE improves risk prediction.

Ratio of early transmitral inflow velocity to early diastolic strain rate predicts atrial fibrillation following acute myocardial infarction.

The ratio of early transmitral filling velocity to early diastolic strain rate (E/SRe) has been proposed as a new non-invasive measurement of left ventricular filling pressure. We aimed to investigate the ability of E/SRe to predict atrial fibrillation (AF) after ST-elevation myocardial infarction (STEMI). This was a prospective cohort study of patients (n = 369) with STEMI. Patients underwent an echocardiographic examination a median of two days after pPCI. By echocardiography, transmitral early filling velocity (E) was measured by pulsed-wave Doppler, and early diastolic strain rate (SRe) was measured by speckle tracking of the left ventricle. E was indexed to SRe and the early myocardial relaxation velocity (e') to obtain the E/SRe and E/e', respectively. The endpoint was new-onset AF. During follow-up (median 5.6 years, IQR: 5.0-6.1 years), 23 (6%) of the 369 patients developed AF. In unadjusted analyses, both E/SRe and E/e' were significantly associated with AF [E/SRe: HR = 1.06; (1.03-1.10); p < 0.001, per 10 increase] and [E/e': HR = 1.11 (1.05-1.17); p < 0.001, per 1 increase] and had equal Harrell's C-statistic of 0.71. However, only E/SRe remained an independent predictor after multivariable adjustments for clinical and echocardiographic parameters [E/SRe: HR = 1.06 (1.00-1.11); p = 0.044, per 10 increase]. E/SRe was further significantly associated with AF in patients with E/e' < 14 HR = 1.09 (1.01-1.17); p = 0.030, per 10 increase), also after multivariable adjustments. E/SRe is an independent predictor of AF in STEMI patients, even in subjects with seemingly normal filling pressure.

Even Mild Mitral Regurgitation is Associated with Incident Atrial Fibrillation in the General Population.

BACKGROUND: Mitral regurgitation (MR) can be difficult to quantify. We sought to investigate whether the MR jet area to left atrial (LA) area ratio (MR/LA-ratio) method for quantifying MRs can be used to predict incident AF in the general population. METHODS: The study included 4,466 participants from the 5th Copenhagen City Heart Study, a prospective general population study, who underwent transthoracic echocardiography. MR jet area was measured and indexed to LA area. The endpoint was incident AF. RESULTS: MR was quantified in 4,042 participants (mean age: 57 years, 43% men). Of these, 198 (4.9%) developed AF during a median follow-up period of 5.3 years (IQR: 4.4-6.1 years). MR was present in 1,938 participants (48%) including 1593 (39%) trace/mild MRs (MR/LA-ratio ≤ 20% and ≤4 cm2). In unadjusted analysis, MR/LA-ratio was associated with incident AF (HR: 1.06 (1.00-1.13), p = 0.042 per 5% increase) but not after adjusting for CHARGE-AF score. However, the association was modified by age (p for interaction = 0.034), such that MR/LA-ratio was associated with AF only in participants ≤73 years. In these participants, MR/LA-ratio was independently associated with AF after adjusting for CHARGE-AF score (HR: 1.14 (1.06-1.24), p = 0.001, per 5% increase). This finding persisted when restricting the analysis to participants without moderate or severe MR and normal LA size (HR: 1.35 (1.09-1.68), p = 0.005, per 5% increase). CONCLUSION: Mitral regurgitation, including even trace regurgitations quantified by MR/LA-ratio is independently associated with incident AF in individuals ≤73 years of age.

Interplay between natriuretic peptides and left atrial mechanics and the relation to recurrence of atrial fibrillation following catheter ablation.

The relationship between natriuretic peptides and atrial distension is not fully understood. We sought to examine their interrelationship and how they relate to atrial fibrillation (AF) recurrence following catheter ablation. We analyzed patients enrolled in the AMIO-CAT trial (amiodarone vs. placebo for reducing AF recurrence). Echocardiography and natriuretic peptides were assessed at baseline. Natriuretic peptides included mid-regional proANP (MR-proANP) and N-terminal proBNP (NT-proBNP). Atrial distension was assessed by left atrial strain measured by echocardiography. The endpoint was AF recurrence within 6 months after a 3-month blanking period. Logistic regression was used to assess the association between log-transformed natriuretic peptides and AF. Multivariable adjustments were made for age, gender, randomization, and left ventricular ejection fraction. Of 99 patients, 44 developed AF recurrence. No differences in natriuretic peptides nor echocardiography were observed between the outcome groups. In unadjusted analyses, neither MR-proANP nor NT-proBNP were significantly associated with AF recurrence [MR-proANP: OR = 1.06 (0.99-1.14), per 10% increase; NT-proBNP: OR = 1.01 (0.98-1.05), per 10% increase]. These findings were consistent after multivariable adjustments. However, atrial strain significantly modified the association between MR-proANP and AF (p for interaction = 0.009) such that MR-proANP was associated with AF in patients with high atrial strain [OR = 1.24 (1.06-1.46), p = 0.008, per 10% increase] but not in patients with low atrial strain. In patients with high atrial strain, an MR-proANP > 116 pmol/L posed a fivefold higher risk of AF recurrence [HR = 5.38 (2.19-13.22)]. Atrial natriuretic peptide predicts AF recurrence in patients with preserved atrial distension. Assessing atrial strain may assist the interpretation of natriuretic peptides.

Age- and sex-based normal reference ranges of the cardiac time intervals: the Copenhagen City Heart Study.

BACKGROUND: Color tissue Doppler imaging (TDI) M-mode can be used to measure the cardiac time intervals including the isovolumic contraction time (IVCT), the left ventricular ejection time (LVET), the isovolumic relaxation time (IVRT), and the combination of all the cardiac time intervals in the myocardial performance index (MPI) defined as [(IVCT + IVRT)/LVET]. The aim of this study was to establish normal age- and sex-based reference ranges for the cardiac time intervals. METHODS AND RESULTS: A total of 1969 participants free of cardiovascular diseases and risk factors from the general population with limited age range underwent an echocardiographic examination including TDI. The median age was 46 years (25th-75th percentile: 33-58 years), and 61.5% were females. In the entire study population, the IVCT was observed to be 40 ± 10 ms [95% prediction interval (PI) 20-59 ms], the LVET 292 ± 23 ms (95% PI 248-336 ms), the IVRT 96 ± 19 ms (95% PI 59-134 ms) and MPI 0.47 ± 0.09 (95% PI 0.29-0.65). All the cardiac time intervals differed significantly between females and males. With increasing age, the IVCT increased in females, but not in males. The LVET did not change with age in both sexes, while the IVRT increased in both sexes with increasing age. Furthermore, we developed regression equations relating the heart rate to the cardiac time intervals and age- and sex-based normal reference ranges corrected for heart rate. CONCLUSION: In this study, we established normal age- and sex-based reference ranges for the cardiac time intervals. These normal reference ranges differed significantly with sex.

Normal Values and Reference Ranges for the Ratio of Transmitral Early Filling Velocity to Early Diastolic Strain Rate: The Copenhagen City Heart Study.

BACKGROUND: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has recently emerged as a measure of left ventricular filling pressure. Reference values are needed for this new parameter for it to be used clinically. METHODS: Healthy participants from a prospective general population study, the Fifth Copenhagen City Heart Study, were assessed to establish reference values for E/e'sr derived from two-dimensional speckle-tracking echocardiography. The prevalence of abnormal E/e'sr was assessed in participants with cardiovascular risk factors or specific diseases. RESULTS: The population comprised 1,623 healthy participants (median age, 45; interquartile range, 32-56; 61% female). The upper reference limit for E/e'sr in the population was 79.6 cm. Following multivariable adjustment, male participants exhibited significantly higher E/e'sr than female participants (upper reference limit for male participants, 83.7 cm; for female participants, 76.5 cm). For both sexes, E/e'sr increased in a curvilinear fashion with age such that the largest increases in E/e'sr were observed in participants >45 years. In the entire CCHS5 population with E/e'sr available (n = 3,902), increasing age, body mass index, systolic blood pressure, male sex, estimated glomerular filtration rate, and diabetes were associated with E/e'sr (all P < .05). Total cholesterol was associated with a less steep increase in E/e'sr. Abnormal E/e'sr was seldomly observed in participants with normal diastolic function but became more frequent in participants with increasing grades of diastolic dysfunction (normal, mild, moderate, severe [abnormal E/e'sr for each grade: 4.4% vs 20.0% vs 16.2% vs 55.6%, respectively]). CONCLUSION: The E/e'sr differs between sexes and is age dependent such that E/e'sr increases with advancing age. Therefore, we established sex- and age-stratified reference values for E/e'sr.