Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement.

BACKGROUND: The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood. METHODS: Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1). RESULTS: There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE. CONCLUSION: An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF.

The reduction of the left ventricular long-axis early diastolic peak velocity (e') evident by early-middle age occurs in the absence of aging-related slowing of active relaxation.

PURPOSE: A decrease in the left ventricular (LV) long-axis early diastolic peak velocity (e') is evident by early-middle age, but it is unknown to what extent this decrease is due to slowing of the speed of active relaxation versus a reduction in LV long-axis excursion during early diastole (EDExc). METHODS: Pulsed-wave tissue Doppler imaging (TDI) signals were acquired from the septal and lateral borders of the mitral annulus in 62 healthy adult subjects of age 18-45 years. EDExc and LV systolic excursion (SExc) were measured as the integrals of the respective TDI signals. The speed of active relaxation was indirectly assessed using time interval measurements related to the TDI early diastolic signal, including the isovolumic relaxation time (IVRT'), the acceleration time (EDAT), and the duration (EDDur). Multiple linear regression analyses were performed to identify the relationships between e', age, EDExc, SExc, and time intervals. RESULTS: The findings were similar for both LV walls. Age was negatively correlated with e' and EDExc, but was not correlated with SExc, IVRT', EDAT, or EDDur. The closest correlate of EDExc was SExc, and EDExc was independently correlated with both SExc and age. e' was also positively correlated with SExc, but the closest correlate of e' was EDExc, and when combined with EDExc, EDDur became an independent predictor of e'. CONCLUSION: The aging-related decrease in e' evident by early-middle age occurs in the absence of aging-related slowing of active relaxation and therefore can be largely attributed to the accompanying reduction in EDExc.

Dobutamine effects on systolic and diastolic left ventricular long-axis excursion and timing - significance for the interpretation of s' and e'.

BACKGROUND: Dobutamine effects on the relationships of the peak velocity of left ventricular (LV) long-axis systolic motion (s') with systolic excursion (SExc), systolic duration (SDur) and heart rate, of LV long-axis early diastolic excursion (EDExc) with SExc, and of the peak velocity of LV long-axis early diastolic motion (e') with EDExc, early diastolic duration (EDDur) and isovolumic relaxation time (IVRT') are unknown. METHODS: Two groups of adult subjects, one young and healthy (n = 10), and one with impaired LV long-axis function (n = 10), were studied, with the aim of identifying consistent findings for the two groups and for the septal and lateral walls. Dobutamine was infused at doses of 5 and 10 µg/kg/min. The relationships between tissue Doppler imaging (TDI) variables acquired before and during dobutamine infusion were analysed using mixed effect multivariate regression modelling. RESULTS: In both groups, heart rate increased and SDur decreased during dobutamine infusion, and there were independent inverse correlations of SDur with heart rate and dobutamine dose. In contrast, there was no change in EDDur during dobutamine infusion, and no consistent changes in IVRT' independent of heart rate. s' was positively correlated with SExc and inversely correlated with SDur, and there were positive correlations between EDExc and SExc and between e' and EDExc. CONCLUSION: Dobutamine increases s' due to effects on both systolic excursion and duration and it increases e' due to the associated increases in systolic and early diastolic excursion. A lack of effect on diastolic times does not support the presence of a lusitropic effect of dobutamine.

Determinants of left ventricular structure, filling and long axis function in systemic sclerosis.

BACKGROUND: Abnormalities of left ventricular (LV) structure, filling and long-axis function have all been reported in subjects with systemic sclerosis (SSc) and a normal LV ejection fraction (EF), but previous study findings have not been consistent. The aim of this study was to identify factors which could have confounded the analyses in previous studies of SSc, and in particular to consider the variables of body surface area (BSA), sex, age, heart rate, blood pressure (BP), disease duration (DD), disease type (limited versus diffuse) and interstitial lung disease (ILD). METHODS: Echocardiography was performed on 100 subjects with SSc (79 women; age 56±15 years) with a LVEF ≥50% and free of pulmonary arterial hypertension, coronary artery disease, more than mild valvular heart disease and atrial fibrillation. Measurements were performed of the LV end-diastolic dimension (LVEDD) and septal wall thickness (SWT), the transmitral Doppler E, A and deceleration time (DT), and the peak systolic (s') and early diastolic (e') LV long-axis velocities. Multivariate analyses were performed to investigate correlations of the above LV variables with BSA, sex, age, heart rate, BP, DD, disease type, and the presence of ILD. RESULTS: DD varied between 0.1 and 41.2 years, 25% had diffuse and 75% had limited disease, and 37% had ILD. SWT and LVEDD were positively correlated with BSA, SWT was also positively correlated with age and larger in males, and LVEDD was larger in diffuse disease. Age was positively correlated with A and DT, and inversely correlated with E and E/A, and heart rate was inversely correlated with E and E/A. None of E, A, E/A, or DT were independently associated with DD or disease type. Septal and lateral LV wall s' and e' were all inversely correlated with age, and there was a small independent contribution to the prediction of lateral s' from DD, but no association of either s' or e' with disease type. The presence of ILD was not a predictor of any of the LV variables. CONCLUSION: In SSc there are associations of sex, body size, age and disease type with LV structural variables, of age and heart rate with E/A, and of age with both systolic and early diastolic LV long-axis velocities. Appropriate adjustment for these variables could help to resolve current uncertainties regarding SSc effects on the left ventricle.

Changes in left ventricular size, geometry, pump function and left heart pressures during healthy aging.

There are cross-sectional and longitudinal imaging studies using echocardiography and cardiac magnetic resonance in healthy adult subjects which have demonstrated associations of left ventricular (LV) structure and pump function with age. There are also cross-sectional data regarding the relationships of age with invasively measured left heart chamber pressures. Increasing age is associated with decreases in LV end-diastolic volume (LVEDV), end-systolic volume (LVESV), end-diastolic length (LVEDL), stroke volume (SV) and cardiac output (CO), and increases in relative wall thickness (RWT), LV mass/LVEDV ratio (LVMVR) and ejection fraction (LVEF). Older age is not accompanied by a change in mean left atrial (LA) pressure, but there is both direct and indirect evidence which suggests that LV end-diastolic pressure (LVEDP) increases with age. LVEDV remains lower in older than younger subjects during fluid infusion and the resulting increases in LA pressure. The combination of an increase in LVEF with reductions of both SV and CO demonstrates an age-related increase in divergence between LVEF and LV pump function. A lower LVEDV in older compared to younger subjects can be characterized as an aging-related decrease in LV capacity, with the higher LVEDP in older subjects also indicating a reduction of preload reserve.

Left ventricular long-axis function in hypertrophic cardiomyopathy - Relationships between e`, early diastolic excursion and duration, and systolic excursion.

BACKGROUND: The peak velocity of early diastolic mitral annular motion (e`) is believed to provide sensitive detection of left ventricular (LV) diastolic dysfunction in hypertrophic cardiomyopathy (HCM), but other aspects of LV long-axis function in HCM have received less attention. Systolic mitral annular excursion (SExc) is also reduced in HCM and must be an intrinsic limitation to the extent of the subsequent motion during diastole. However, the effects of HCM on excursion during early diastole (EDExc) and atrial contraction (AExc), the duration of early diastolic motion (EDDur), and the relationships of EDExc with SExc, and of e`with EDExc and EDDur, are all unknown. METHODS: The study group was 22 subjects with HCM and there were 22 age and sex matched control subjects. SExc, EDExc, e`, AExc and EDDur were measured from pulsed wave tissue Doppler signals acquired from the septal and lateral walls. In the combined group of HCM and control subjects, multivariate analyses were performed to identify independent predictors of EDExc and e`for both LV walls. RESULTS: SExc, EDExc and e`were all lower, and EDDur was longer in the HCM group compared to the control group for both LV walls (p<0.05 for all). In contrast, AExc was lower for the septal wall in the HCM group (p<0.05), but not different between the groups for the lateral wall. In regression analyses of the combined group, EDExc was positively correlated with SExc, and SExc explained 57-86% of the variances in septal and lateral EDExc, e`was positively correlated with EDExc, and EDExc explained 58-68% of the variances of e`, whereas the combination of EDExc with EDDur explained 87-92% of the variances in e`. A diagnosis of HCM was not an independent predictor of EDExc when in combination with SExc, but was a minor contributor to the prediction of e`in combination with EDExc and EDDur. CONCLUSION: In HCM, the decrease in LV longitudinal contraction is the major mechanism accounting for a lower EDExc, the lower e`is accounted for by contributions from the lower EDExc and prolongation of early diastolic motion, and there is no atrial compensation for the reduction of long-axis contraction.

Understanding preload and preload reserve within the conceptual framework of a limited range of possible left ventricular end-diastolic volumes.

Preload has been variously defined, but if there is to be a direct relationship with activity of the Frank-Starling mechanism in its action to increase the force and extent of contraction, preload must directly reflect myocardial stretch. The Frank-Starling mechanism is activated during any stretch of a cardiac chamber beyond its resting size, which is present immediately before contraction. Every left ventricle has an intrinsic and limited range of possible volumes at end diastole. There is a curvilinear relationship between left ventricular (LV) end-diastolic pressure (LVEDP) and LV end-diastolic volume (LVEDV), and, at maximal or near maximal LVEDV, there will be a high LVEDP. Within the possible range, the LVEDV will be determined by the extent of filling, any change in LVEDV will result in changed activity of the Frank-Starling mechanism, and change in LVEDV might, therefore, be considered to represent change in preload. On the other hand, it is the difference between the current and the maximal possible LVEDV (or the preload reserve) that may be of the most clinical relevance. There is a reciprocal relationship between preload and preload reserve, with minor or absent LV preload reserve indicating that there will be either minimal or no increase in stroke volume following intravenous fluid administration. As left atrial pressure can remain within the normal range when the LVEDP is elevated, it is LVEDP, and not left atrial pressure, that provides the most reliable guide to preload reserve in an individual at a specific period in time.

Relationships of global longitudinal strain with s`, long-axis systolic excursion, left ventricular length and heart rate.

BACKGROUND: Longitudinal left ventricular (LV) contraction can be impaired in the presence of a normal LV ejection fraction (LVEF), and abnormalities have been reported in global longitudinal strain (GLS), long-axis systolic excursion (SExc), and the peak systolic velocity (s`) of mitral annular motion using tissue Doppler imaging (TDI). However, the relationships of GLS with s` and SExc have not been systematically evaluated in subjects with a normal LVEF, and whether these relationships might be affected by variations in LV end-diastolic length (LVEDL) and heart rate is unknown. METHODS: We investigated the univariate and multivariate correlations of GLS with TDI measurements of s` and SExc (both using averages of the septal and lateral walls), LVEDL and heart rate in subjects with a normal LVEF (>50%) but a low peak early diastolic mitral annular velocity (septal e`≤ 7.0 cm/s and lateral e`≤ 9 cm/s), and thus an increased risk of a future cardiac event. RESULTS: 84 subjects (age 66±8 years, 29 males) with a LVEF of 62±6% and GLS of -17.5±2.3% were studied. On univariate analysis the absolute value of GLS was positively correlated with s`(r = 0.28, p<0.01) and SExc (r = 0.50, p<0.001) and inversely correlated with heart rate (r = -0.36, p = 0.001), but was not correlated with LVEDL (r = -0.15). In multivariate models, SExc explained more of the variance in GLS than s`, and absolute GLS was not only positively correlated with SExc, but also inversely correlated with LVEDL. Heart rate was an independent inverse correlate of GLS in conjunction with LVEDL and either s` or SExc, but made a larger contribution in models which included s`. Interobserver correlations were close for s` and SExc (r = 0.89-0.93), but only moderate for GLS (r = 0.71). CONCLUSION: In subjects with a normal LVEF but reduced e`, the absolute value of GLS is more closely related to SExc than s`, and is also independently and inversely related to LVEDL and heart rate. Measurement of SExc may provide a useful additional or alternative technique to GLS for the assessment of LV long-axis function.

Left ventricular structural and functional changes in Friedreich ataxia - Relationship with body size, sex, age and genetic severity.

INTRODUCTION: Although a concentric pattern of left ventricular (LV) geometry appears to be common in Friedreich ataxia (FRDA), there is no accepted method for diagnosing LV abnormalities in FRDA, sex and body size have often not been taken into consideration, and it has not been clear whether children and adults should be classified using the same criteria. The aim of this study was to better define the LV geometric changes in FRDA with respect to sex, body size and subject age, and to investigate the relationship of LV changes with genetic severity, as assessed by GAA repeat length within the shorter allele of the FXN gene (GAA1). METHODS: Echocardiography was performed in 216 subjects (68 children, 148 adults), measurements were made at end-diastole of LV internal diameter (LVEDID), septal wall thickness (SWT), LV length (LVEDL) and LV volume (LVEDV), and calculations were made of relative wall thickness (RWT), LV mass and LV ejection fraction (LVEF). RESULTS: The most common LV abnormalities in both adults and children with FRDA were increases in RWT and age-normalized RWT. In adults with a normal LVEF, all LV variables other than RWT were larger in males independent of body surface area (BSA), and all LV variables other than SWT and RWT were positively correlated with BSA. After adjustment for sex and BSA, GAA1 was a positive correlate of SWT and RWT (but not of LV mass), and was an inverse correlate of LVEDID, LVEDL and LVEDV. In children with a normal LVEF, SWT, LV mass and LVEDL were larger in males than females after adjusting for BSA, and in combination with sex, BSA was a positive correlate of all the LV variables except SWT and RWT. In children there were no correlations of GAA1 with any of the LV variables. CONCLUSION: In FRDA, increases in RWT and age-normalized RWT are the most frequent LV structural abnormalities, sex and body size are important determinants of most other LV structural variables in both children and adults, and increased genetic severity is associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with LV size or wall thickness in children.

Correction: Aging and the relationships between long-axis systolic and early diastolic excursion, isovolumic relaxation time and left ventricular length-Implications for the interpretation of aging effects on e`.

[This corrects the article DOI: 10.1371/journal.pone.0210277.].

Aging and the relationships between long-axis systolic and early diastolic excursion, isovolumic relaxation time and left ventricular length-Implications for the interpretation of aging effects on e`.

BACKGROUND: Both the left ventricular (LV) long-axis peak early diastolic lengthening velocity (e`) and long-axis early diastolic excursion (EDExc) decrease with age, but the mechanisms underlying these decreases are not fully understood. The aim of this study was to investigate the relative contributions to aging-related decreases in e`and EDExc from LV long-axis systolic excursion (SExc), isovolumic relaxation time (IVRT, as a measure of the speed of relaxation) and LV end-diastolic length (LVEDL). METHODS: The study group was 50 healthy adult subjects of ages 17-75 years with a normal LV ejection fraction. SExc, EDExc, e`and IVRT were measured from pulsed wave tissue Doppler signals acquired from the septal and lateral walls. Multivariate modelling was performed to identify independent predictors of EDExc and e`which were consistent for the septal and lateral walls. RESULTS: EDExc decreased with age and the major determinant of EDExc was SExc, which also decreased with age. There was also a decrease of e`with age, and the major determinant of e`was EDExc. IVRT decreased with age and on univariate analysis was not only inversely correlated with EDExc and e`, but also with SExc. IVRT was only a minor contributor to models of EDExc which included SExc, and was an inconsistent contributor to models of e`which included EDExc. LVEDL decreased with age independent of sex and body size, and was positively correlated with SExc, EDExc and e`. CONCLUSION: Major mechanisms underlying the decrease in e`seen during aging are the concomitant decreases in long-axis contraction and early diastolic excursion, which are in turn related in part to long-axis remodelling of the left ventricle. After adjusting for the extent of systolic and early diastolic excursion, slowing of relaxation, as reflected in prolongation of the IVRT, makes no more than a minor contribution to aging-related decreases in EDExc and e`.

Differences in the determinants of right ventricular and regional left ventricular long-axis dysfunction in Friedreich ataxia.

BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition which also has effects on the heart. In 96% of affected individuals FRDA is due to homozygosity of a GAA repeat expansion in intron 1 of the frataxin (FXN) gene. The number of GAA repeats have been shown to relate to disease severity in FRDA, this thought to be via an inverse relationship of GAA repeat number and cellular frataxin levels. We investigated the effects of FRDA on regional long axis function of the left and right ventricles, and also the relationship of long axis systolic (s`) and early diastolic (e`) peak velocities with GAA repeat number on the shorter (GAA1) and longer FXN alleles (GAA2). METHODS: The study group of 78 adult subjects (age 32±9 years) with FRDA and normal left ventricular (LV) ejection fraction were compared to 54 healthy control subjects of similar age, sex and body size. Tissue Doppler imaging (TDI) signals were recorded at the mitral annulus for measurement of s`and e`of the septal, lateral, anterior and inferior walls and at the tricuspid annulus for measurement of right ventricular (RV) s`and e`. RESULTS: All the regional LV s`and e`, and both RV s`and RV e`, were lower in individuals with FRDA compared to controls (p<0.001 for all). On multivariate analysis, which included LV septal wall thickness (SWT), RV s`and RV e`were both inversely correlated with GAA1 (ß = -0.32 & -0.33, respectively, p = 0.01), but not with GAA2, whereas anterior and lateral s`were both inversely correlated with GAA2 (ß = -0.25 and ß = -0.28, p = 0.02) but not with GAA1. Increasing SWT was the most consistent LV structural correlate of lower s`and e`, whereas age was a consistent inverse correlate of e`but not of s`. CONCLUSION: There are generalized abnormalities of both LV regional and RV long axis function in FRDA, but there are also regional differences in the association of this dysfunction with the smaller and larger GAA repeats in the FXN gene.

Left ventricular long axis tissue Doppler systolic velocity is independently related to heart rate and body size.

BACKGROUND: The physiological factors which affect left ventricular (LV) long-axis function are not fully defined. We investigated the relationships of resting heart rate and body size with the peak velocities and amplitudes of LV systolic and early diastolic long axis motion, and also with long-axis contraction duration. METHODS: Two groups of adults free of cardiac disease underwent pulsed-wave tissue Doppler imaging at the septal and lateral mitral annular borders. Group 1 (n = 77) were healthy subjects <50 years of age and Group 2 (n = 65) were subjects between 40-80 years of age referred for stress echocardiography. Systolic excursion (SExc), duration (SDur) and peak velocity (s') and early diastolic excursion (EDExc) and peak velocity (e') were measured. RESULTS: SExc was not correlated with heart rate, height or body surface area (BSA) for either LV wall in either group, but SDur was inversely correlated with heart rate for both walls and both groups, and after adjustment for heart rate, males in both groups had a shorter septal SDur. Septal and lateral s` were independently and positively correlated with SExc, heart rate and height in both groups, independent of sex and age. There were no correlations of heart rate, height or BSA with either e` or EDExc for either wall in either group. CONCLUSION: Heart rate and height independently modify the relationship between s` and SExc, but neither are related to EDExc or e`. These findings suggest that s` and SExc cannot be used interchangeably for the assessment of LV long-axis contraction.

Possible Mechanisms Underlying Aging-Related Changes in Early Diastolic Filling and Long Axis Motion-Left Ventricular Length and Blood Pressure.

BACKGROUND: The transmitral E wave and the peak velocity of early diastolic mitral annular motion (e`) both decrease with age, but the mechanisms underlying these age-related changes are incompletely understood. This study investigated the possible contributions of blood pressure (BP) and left ventricular end-diastolic length (LVEDL) to age-related reductions in E and e`. METHODS: The study group were 82 healthy adult subjects <55 years of age who were not obese or hypertensive. Transmitral flow and mitral annular motion were recorded using pulsed-wave Doppler. LVEDL was measured from the mitral annular plane to the apical endocardium. RESULTS: Age was positively correlated with diastolic BP and septal wall thickness (SWT), inversely correlated with LVEDL (ß = -0.25) after adjustment for sex and body surface area, but was not related to left ventricular end-diastolic diameter (LVEDD). Age was also inversely correlated with E (r = -0.36), septal e`(r = -0.53) and lateral e`(r = -0.53). On multivariable analysis, E was inversely correlated with diastolic BP and LVEDD, septal e`was inversely correlated with diastolic BP and positively correlated with SWT and LVEDL, after adjusting for body mass index, whilst lateral e`was inversely correlated with diastolic BP and positively correlated with LVEDL. CONCLUSION: The above findings are consistent with higher BP being a contributor to age-related reductions in both E and e`and shortening of LVEDL with age being a contributor to the age-related reduction in e`. An implication of these findings is that slowing of myocyte relaxation is unlikely to be the sole, and may not be the main, mechanism underlying age-related decreases in E and e`.

Benign Cardiac Effects of Hemoglobin H Disease.

BACKGROUND/AIMS: Hemoglobin H (HbH) disease is associated with iron overload, but whether this results in serious cardiac or vascular sequelae is unresolved. METHODS: We identified 39 adult subjects (age 42 ± 12 years, 13 men) with HbH disease who had undergone echocardiography, 27 of whom had also undergone cardiac and liver magnetic resonance assessment of iron loading using T2*-weighted imaging. RESULTS: None of the subjects had a history of heart failure or arrhythmias. There were 13/39 subjects with a ferritin level within the sex-based normal range and only 4/39 had ferritin >1,000 ng/ml. Left ventricular (LV) and left atrial dilatation was common, but LV ejection fraction was normal (≥55%) in all subjects. Age was positively correlated with log ferritin in the 27 nontransfused subjects (r = 0.43) and was inversely correlated with the transmitral E wave and E/A ratio (r = -0.69 and r = -0.79, respectively), but no relation of log ferritin with E or E/A was evident. The peak tricuspid regurgitation velocity was normal in 24/29 subjects for whom this was obtained, and it was no more than mildly elevated in the other 5. None of the tested subjects had an abnormal cardiac T2* reading, but half had evidence of liver iron loading. CONCLUSION: No myocardial iron loading or serious cardiac or vascular sequelae were identified in this cohort with HbH disease.

"Left ventricular filling pressure(s)" - Ambiguous and misleading terminology, best abandoned.

The use of the terms "left ventricular filling pressure" and "left ventricular filling pressures" is widespread in the cardiology literature, but the meanings ascribed to these terms have not been consistent. Left ventricular end-diastolic pressure (LVEDP) and mean left atrial pressure (LAP) cannot be used interchangeably as they will often differ in magnitude in the presence of cardiac disease and they also have different clinical significance. LVEDP is the best pressure to use when considering left ventricular function, whereas mean LAP is the most relevant pressure when considering the tendency to pulmonary congestion. The mean LAP is also the most relevant pressure for determining whether pulmonary hypertension has a left heart (post-capillary) component. If only a left ventricular pressure tracing is available then a technique to measure the mean left ventricular diastolic pressure is the best option for estimating the mean LAP. If only right heart pressures are available then the pulmonary artery end-diastolic pressure will provide a reasonable estimate of LVEDP, but only when the heart and pulmonary circulation are normal. If there is mitral valve disease, left ventricular disease or pulmonary hypertension the LVEDP cannot be estimated from right heart pressures. The problem of the ambiguity of "filling pressure (s)" is readily solved by the abandonment of this term and the use of either LVEDP or mean LAP as appropriate.