Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta.

AIMS: Oestrogen receptor alpha (ERα) and beta (ERß) are involved in the regulation of pathological myocardial hypertrophy (MH). We hypothesize that both ER are also involved in physiological MH. Therefore, we investigated the role of ER in exercise-induced physiological MH in loss-of-function models and studied potential mechanisms of action. METHODS AND RESULTS: We performed 1 and 8 weeks of voluntary cage wheel running (VCR) with male and female C57BL/6J wild-type (WT), ERα- and ERß-deleted mice. In line with other studies, female WT mice ran more than males (P ≤ 0.001). After 8 weeks of VCR, both sexes showed an increase in left ventricular mass (females: P ≤ 0.01 and males: P ≤ 0.05) with more pronounced MH in females (P < 0.05). As previously shown, female ERα-deleted mice run less than female WT mice (P ≤ 0.001). ERß-deleted mice showed similar running performance as WT mice (females vs. male: P ≤ 0.001), but did not develop MH. Only female WT mice showed an increase in phosphorylation of serine/threonine kinase (AKT), ERK1/2, p38-mitogen-activated protein kinase (MAPK), and ribosomal protein s6, as well as an increase in the expression of key regulators of mitochondrial function and mitochondrial respiratory chain proteins (complexes I, III, and V) after VCR. However, ERß deletion abolished all observed sex differences. Mitochondrial remodelling occurred in female WT-VCR mice, but not in female ERß-deleted mice. CONCLUSION: The sex-specific response of the heart to exercise is modulated by ERß. The greater increase in physiological MH in females is mediated by induction of AKT signalling, MAPK pathways, protein synthesis, and mitochondrial adaptation via ERß.

Assessment of atrial electromechanical delay in children with acute rheumatic fever.

PURPOSE: There may be an increase in the risk of atrial arrhythmia due to left atrial enlargement and the influence on conduction system in acute rheumatic fever. The aim of this study is to investigate atrial electromechanical delay and P-wave dispersion in patients with acute rheumatic fever. PATIENTS: A total of 48 patients diagnosed with acute rheumatic fever and 40 volunteers of similar age, sex, and body mass index were included in the study. The study groups were compared for M-mode echocardiographic parameters, interatrial electromechanical delay, intra-atrial electromechanical delay, and P-wave dispersion. RESULTS: Maximum P-wave duration, P-wave dispersion, and interatrial electromechanical delay were significantly higher in patients with acute rheumatic fever compared with the control group (p < 0.001). However, there was no difference in terms of intra-atrial electromechanical delay (p > 0.05). For patients with acute rheumatic fever, a positive correlation was identified between the left atrium diameter and the P-wave dispersion and interatrial electromechanical delay (r = 0.524 and p < 0.001, and r = 0.351 and p = 0.014, respectively). Furthermore, an important correlation was also identified between the P-wave dispersion and the interatrial electromechanical delay (r = 0.494 and p < 0.001). CONCLUSION: This study shows the prolongation of P-wave dispersion and interatrial electromechanical delay in acute rheumatic fever. Left atrial enlargement can be one of the underlying reasons for the increase in P-wave dispersion and interatrial electromechanical delay.

Cardiovascular assessment of asymptomatic patients with juvenile-onset localized and systemic scleroderma: 10 years prospective observation.

OBJECTIVES: The aim of the present study was non-invasive evaluation of the cardiovascular system in asymptomatic young adult patients with juvenile localized scleroderma (JLS) and juvenile systemic sclerosis (JSS). METHODS: A group of 34 consecutive children with scleroderma were prospectively observed in the study. The control group (CG) consisted of 20 healthy subjects. In each subject 12-lead electrocardiographic, echocardiographic, ECG Holter, and ambulatory blood pressure monitoring examinations were performed at the baseline visit and after 10 years. Additionally, B-type natriuretic peptide (BNP) concentrations were measured after 10 years. RESULTS: Examinations were performed in 13 patients with JLS and 15 with JSS at the final visit. Two children had died (one from each group). Four patients were alive but refused the final visit. After 10 years, a higher prevalence of ventricular extrasystoles (p = 0.01) and an elevated pulmonary arterial pressure (JLS: p = 0.04, JSS: p = 0.03) were observed in both groups, but in comparison with the controls there was no significant difference at the final visit. In JLS patients more cases of left ventricle diastolic dysfunction, hypertension, and sinus tachycardia were diagnosed at the final visit (p ≤ 0.05). More atrioventricular block episodes in both groups of scleroderma patients were observed. Over the 10 years, arterial hypertension was diagnosed in three patients from the JLS group and in two with JSS. There were no significant differences in BNP concentrations at the final visit. CONCLUSIONS: The results of the present study show that juvenile scleroderma seems to be more benign than adult-onset disease. This observational study shows subclinical, not severe, cardiac abnormalities in adult patients with juvenile-onset disease.

Ressonância magnética cardíaca na cardiomiopatia dilatada: atualidades / Cardiac magnetic resonance in dilated cardiomyopathy: an update

JUSTIFICATIVA E OBJETIVOS: A cardiomiopatia dilatada(CMD) é a mais comum das cardiomiopatias, compreendendo mais de 90% de todos os casos. O seu diagnóstico é feito, sobretudo,com a utilização da ecocardiografia, a qual apresenta algumas limitações quanto à identificação da etiologia. A ressonância magnética cardíaca (RMC) tem se destacado como exame coadjuvante, permitindo melhor caracterização morfofuncional e tecidual do músculo cardíaco. O objetivo deste estudo foi descrevero papel da RMC no diagnóstico e avaliação das diversas causas de CMD.CONTEÚDO: A RMC apresentou bons resultados na aplicaçã oclínica em diversas causas de CMD, não possuindo capacidade de diferenciar todos os seus tipos, porém, contribuindo para a presunção diagnóstica.CONCLUSÃO: Com o avanço tecnológico da RMC, múltiplas indicações clínicas têm surgido em algumas ocasiões, com um aspecto complementar a determinados exames, em outras, como solução de dilemas diagnósticos. Tudo isso com acurácia superior aos demais métodos de imagem, poucas contraindicações e mínimos riscos de efeitos adversos.(AU)

BACKGROUND AND OBJECTIVES: Dilated cardiomyopathy (DCM) is the most common cause of cardiomyopathies,including more than 90% of all cases. Its diagnostic is done using, especially, echocardiography; which presents some limitations regarding the etiology's identification. Cardiac magnetic resonance (CMR) has been very useful as a more precise study, allowing better characterization of myocardium tissue and morphology. The objective of this article was to describe the role of the CMR in the diagnosis and evaluation of the diverse causes of DCM.CONTENTS : The CMR presented good results in the clinical applicationin diverse causes of DCM, not having capacity to differentiate all their types; however, better contributing to the diagnostic and patients follow up.CONCLUSION: With the technological development of CMR, several clinical indications have been created, in a few occasions with a complementing aspect to certain exams, in others with solutions of diagnostic dilemmas. All with higher accuracy in comparison to others image modalities, few contraindications and minimum adverse risks effects.(AU)

Real-time three-dimensional echocardiographic assessment of left ventricular remodeling index in patients with hypertensive heart disease and coronary artery disease.

Left ventricular remodeling index (LVRI) was assessed in patients with hypertensive heart disease (HHD) and coronary artery disease (CAD) by real-time three-dimensional echocardiography (RT3DE). RT3DE data of 18 patients with HHD, 20 patients with CAD and 22 normal controls (NC) were acquired. Left ventricular end-diastolic volume (EDV) and left ventricular end-diastolic epicardial volume (EDVepi ) were detected by RT3DE and two-dimensional echocardiography Simpson biplane method (2DE). LVRI (left ventricular mass /EDV) was calculated and compared. The results showed that LVRI measurements detected by RT3DE and 2DE showed significant differences inter-groups (P<0.01). There was no significant difference in NC group (P>0.05), but significant difference in HHD and CAD intra-group (P<0.05). There was good positive correlations between LVRI detected by RT3DE and 2DE in NC and HHD groups (r=0.69, P<0.01; r=0.68, P<0.01), but no significant correlation in CAD group (r=0.30, P>0.05). It was concluded that LVRI derived from RT3DE as a new index for evaluating left ventricular remodeling can provide more superiority to LVRI derived from 2DE.

[Correlation between chest radiography and the echocardiogram to evaluate cardiomegaly in patients with systemic arterial hypertension]. / Correlación entre la radiografía de tórax y el ecocardiograma para la valoración de cardiomegalia en pacientes con hipertensión arterial sistémica.

UNLABELLED: The chest radiography is used routinely by the clinician as a tool in the scan of patients with systemic arterial hypertension (SAH) to evaluate the dimensions of the heart. However the highest reported sensitivity for the evaluation of heart growth with this method is 77.3% in contrast to the transthoracic echocardiogram (TTE) that reaches between 90 to 100%. The aim of this study was assess in our population of patients with SAH, the correlation between chest radiography and the TTE in regard to cardiomegaly. PATIENTS AND METHODS: Seventy two patients with SAH and radiological cardiomegaly, graded by measuring the cardiothoracic ratio (CTR), were evaluated by transthoracic echocardiography. The Pearson's and Spearman's correlation coefficients between both methods were assessed. Significance level was set at < 0.05. RESULTS: Forty one (56.9%) patients were women and 31 (43.1%) were men. The age was 62.4 +/- 10 years (43-83 years). Left ventricular concentric hypertrophy (LVCH) was found in 56 (77.8%) patients. In 13 (18%) patients the left ventricular end diastolic diameter (LVEDD) was higher than the normal value. The correlation coefficient between the diastolic ventricular septal thickness (DST) and CTR was 0.285 (p < 0.05) and between the LVEDD and radiological cardiomegaly was 0.203 (p = NS). CONCLUSIONS: In patients with SAH, the radiological evidence of cardiomegaly keeps a correlation with ventricular hypertrophy, but not with ventricular dilation.

Giant left atrium secondary to tight mitral stenosis leading to acquired Lutembacher syndrome: a case report with emphasis on role of echocardiography in assessment of Lutembacher syndrome.

Lutembacher syndrome is an unusual clinical entity of congenital secundum atrial septal defect in combination with rheumatic mitral stenosis. Although this classic form is seldom seen by the adult cardiologist, spontaneous Lutembacher syndrome as discussed later or the iatrogenic variant is not infrequently encountered. The pathophysiologic, clinical, and hemodynamic differences of mitral valve disease in the presence of atrial septal defect compared with isolated mitral stenosis are highlighted in this case review. Special emphasis has also been given to echocardiographic evaluation of this syndrome complex, particularly in the setting of percutaneous mitral valvuloplasty, which produces the iatrogenic form of Lutembacher syndrome.

Serial echocardiographic-Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy. Chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure.

BACKGROUND: Although chronic pressure overload may progress to left ventricular (LV) failure, the pathophysiology of this transition is not well understood. In addition, the effects of chronic angiotensin-converting enzyme (ACE) inhibition on this transition are largely undefined. METHODS AND RESULTS: To examine changes in LV structure and function during the transition to heart failure, rats with LV hypertrophy due to banding of the ascending aorta (LVH, n = 22) and age-matched sham-operated rats (n = 6) were studied 6, 12, and 18 weeks after aortic banding. Two-dimensionally guided transthoracic M-mode echocardiograms and transmitral Doppler spectra were recorded for assessment of LV geometry and systolic and diastolic functions. LVH rats were randomized to no treatment (n = 10) or treatment with the ACE inhibitor fosinopril (50 mg/kg per day, n = 12) after the baseline echocardiogram. Six weeks after banding, LVH rats had increased LV wall thickness with normal cavity dimensions and supranormal endocardial systolic shortening. However, midwall shortening was mildly depressed, and a restrictive diastolic filling pattern was present. After 18 weeks of untreated pressure overload, LV wall thickness was unchanged, but cavity dilation, a fall in endocardial shortening, and further deterioration of diastolic filling were evident. In contrast to untreated LVH rats, the fosinopril-treated rats showed no change in LV diastolic cavity dimension, and systolic and diastolic functions did not deteriorate or improved. Closed chest LV systolic pressures at 18 weeks were not different in LVH or LVH-fosinopril rats (197 versus 198 mm Hg), although end-diastolic pressure was higher in the untreated rats (18 versus 11 mm Hg). Calculated LV systolic wall stress was lower in fosinopril-treated than untreated LVH rats. The severity of LV diastolic filling abnormalities correlated strongly with operating LV chamber stiffness (r = .88, P < .0001). CONCLUSIONS: This model of pressure overload is characterized initially by concentric LV hypertrophy with compensated LV chamber performance; however, markedly abnormal diastolic filling is present. The transition from compensated hypertrophy to early failure is heralded by LV dilation, impairment of systolic function, and progression of the abnormalities in LV filling. Chronic ACE inhibition in rats with supravalvular aortic banding (1) does not change in vivo LV systolic pressure but prevents increased LV cavity size and increased LV wall stress and (2) attenuates impairment of (or improves) both systolic and diastolic functions. The effects of fosinopril could be explained in part by inhibition of an intracardiac renin-angiotensin system.

Echocardiographic assessment of LV mass in rabbits: models of pressure and volume overload hypertrophy.

We describe a method for the noninvasive measurement of left ventricular mass in small animals using two-dimensionally guided M-mode echocardiography. We compared echocardiographic cross-sectional area (CSA) and cubed-based volumetric indexes of left ventricular (LV) mass with postmortem wet weight in renovascular hypertension-induced pressure overload (group I) and acute aortic insufficiency-induced volume overload (group II) models of ventricular hypertrophy. CSA and cubed echocardiographic indexes correlated well with wet weight from a combination of group I and II animals and their controls (r = 0.89, P < 0.001 for both groups). Separate analyses of groups I and II also demonstrated significant relationships between mass indexes and wet weight using CSA and cubed formulas, respectively, in both pressure (r = 0.57, P = 0.01 and r = 0.71, P < 0.001) and volume (r = 0.90 and r = 0.89, P < 0.001) overload models. Echocardiographically predicted LV mass derived from cubed and CSA regression formulas was 89 and 56% sensitive for pressure overload hypertrophy in group I and 100% sensitive (both cubed and CSA methods) for volume overload hypertrophy in group II. Cubed and CSA mass regression formulas were 60 and 80% specific for hypertrophy in group I and 100 and 90% specific in group II. Normalization of predicted LV mass for body weight added little to the overall technique accuracy with measured sensitivities of 83 and 75% and specificities of 92 and 77%, respectively, for cubed and CSA methods. Two-dimensionally guided M-mode echocardiography provides a reasonably accurate method of LV mass determination in rabbits with pressure- or volume-overloaded ventricles.

Assessment of left ventricular dysfunction in acromegalic patients using radionuclide ventriculography parameters.

The left ventricular function of 14 acromegalic patients was investigated using radionuclide ventriculography. After labeling the red blood cells with 750-1,000 MBq 99mTc-pertechnetate, ECG-triggered left anterior oblique images were recorded. Fourier analysis was then performed on the time-activity curve of the left ventricle. The ejection fraction (EF), peak ejection rate, time to peak ejection (TPE), time to end-systole (TES), peak filling rate (PFR), time to peak filling (TPF), 1/3 EF, 1/3 filling fraction (FF), TPE/T, TPF/T and TES/T values (T: time interval for one heart beat) were calculated for each patient. Five patients (35.7%) had clinical cardiovascular symptoms. A decreased EF was observed in 28.5% of the patients. In comparison to the control group, the EF (53.5 +/- 5.5 vs. 60.8 +/- 5% p less than 0.009), 1/3 EF (14.45 +/- 3 vs. 20 +/- 4%, p less than 0.001), 1/3 FF (28.5 +/- 10.6 vs. 41 +/- 11%, p less than 0.02), TPE (158 +/- 33 vs. 132 +/- 35 ms, p less than 0.01), TPE/T (20.2 +/- 5 vs. 16 +/- 3.7, p less than 0.01) and PFR (2.4 +/- 0.5 vs. 2.9 +/- 0.4 EDC/s, p less than 0.005) were significantly different. It was found that TPE was prolonged and the early ejection function was decreased. Diastolic dysfunction was found in 5 (35.7%) patients; 21.4% of the patients had decreased PFR values although they had no cardiac symptom, hypertension and/or cardiomegaly. Scintigraphic parameters did not correlate with the presence of hypertension, cardiomegaly or cardiovascular symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Diastolic disease in left ventricular hypertrophy: comparison of M mode and Doppler echocardiography for the assessment of rapid ventricular filling.

OBJECTIVE: To investigate possible discrepancies between M mode and Doppler echocardiography in assessing early diastolic filling. DESIGN: Forty seven patients with left ventricular hypertrophy due to aortic stenosis and 26 healthy controls with a similar age range were studied by M mode, Doppler, apexcardiography, and phonocardiography. The patients also underwent cardiac catheterisation. M mode echograms were digitised by a computer. Early diastolic filling in both groups as assessed by the two techniques was compared. SETTING: A tertiary cardiac referral centre with facilities for non-invasive and invasive investigations. SUBJECTS: Patients referred for assessment of aortic stenosis who had left ventricular hypertrophy. MAIN OUTCOME MEASURES: Filling velocities on Doppler and rates of wall thinning and dimension increase on M mode. RESULTS: Digitised M mode indices of diastolic filling (peak wall thinning rate 6.4 (3.0) v 10.0 (3.0) cm/s and peak rate of dimension increase 9.3 (3.3) v 16 (4.5) cm/s) in the patients and controls were consistently different. In contrast, the Doppler A/E ratio and peak E wave velocity were not; they varied widely among patients with left ventricular hypertrophy. In part, this variability was because the Doppler A/E ratio, but not the digitised M mode indices, was very sensitive to the abnormalities of isovolumic relaxation frequently present in left ventricular hypertrophy. The Doppler A/E ratio varied similarly with age in both normal and hypertrophied hearts; in the patients with ventricular hypertrophy the peak rate of dimension increase depended on age only, whereas the thinning rate was independent of age in both the patients and controls. Neither the A/E ratio nor the M mode indices could be related to the left ventricular end diastolic pressure or the peak aortic pressure difference. CONCLUSIONS: When Doppler and M mode techniques are used to assess rapid filling in patients with left ventricular hypertrophy the M mode indices are more consistently abnormal. The two methods measure different aspects of left ventricular diastolic function and should be regarded as complementary rather than interchangeable.

Socioeconomic status and morbidity and mortality in hypertensive blacks.

Despite an overall limited range of social and economic opportunities in the recent past, blacks of lower socioeconomic status have experienced marked excesses in hypertension-related burdens compared with their more advantaged peers: the incidence, prevalence, and severity of hypertension and its end-organ sequelae increased with decreasing educational achievement and the 5-year mortality was two times higher for black hypertensives of lower than higher educational achievement under conditions of usual care in U.S. communities in the 1970s. The Stepped Care program of antihypertensive pharmacologic therapy of the HDFP reduced all-cause mortality by 19% for black hypertensive men and 28% for black women. The HDFP also eliminated the association of mortality with educational achievement; the favorable impact of the program was greatest in the group at highest risk, blacks of lowest socioeconomic status.

[The functional assessment of left ventricular hypertrophy in patients with ischemic heart disease]. / Funktsional'naia otsenka gipertrofii levogo zheludochka u bol'nykh ishemicheskoi bolezn'iu serdtsa.

It was established that left ventricular hypertrophy in patients with ischemic heart disease associated with hypertensive disease reflects a functionally more intact myocardium than similar hypertrophy in analogous patients without hypertensive disease. Hypertrophy of the left ventricle in patients with ischemic heart of different severity may be considered an index of myocardial lesion and this should be considered in the treatment tactics.

Non-invasive assessment of left ventricular diastolic function in patients with systemic sclerosis.

To evaluate the extent of left ventricular (LV) diastolic impairment in systemic sclerosis, we examined 30 consecutive patients (15 men and 15 women) with this condition, and compared the findings with the data for 48 age- and sex-matched randomly sampled controls. All patients were investigated by phonocardiography, pulse curve recording, and M-mode echocardiography. Twenty-three of 30 (77%) patients had LV hypertrophy and/or diastolic impairment. Interventricular septum (P = 0.0001), LV posterior wall (P less than 0.05), and the wall thickness to cavity dimension ratio (P less than 0.001) were increased in patients compared to controls, as was LV mass index (P less than 0.002). Five patients had asymmetric septal hypertrophy. LV end-diastolic dimension did not differ between groups. LV distensibility was impaired, as judged from apexcardiographic a/H ratio (P less than 0.05) and from an increased left atrial index (P less than 0.005). LV early filling was impaired, with a reduced left atrial emptying index (P = 0.0001), and a reduced rate of dimension increase in digitized M-mode (P less than 0.02). We found no evidence of impaired LV relaxation. Blood pressure did not differ between patients and controls. With longer duration of the disease, left atrial dimension appeared to increase (r = 0.42, P less than 0.05), while other variables were not related to disease duration. The impaired LV filling was not secondary to systolic dysfunction. We conclude that systemic sclerosis patients have an increased LV wall thickness, with impaired early filling properties and LV distensibility.

[Electrocardiographic indices in the assessment of left ventricular hypertrophy]. / Elektrokardiograficheskie pokazateli v otsenke gipertrofii levogo zheludochka.

The authors compared the electrical activity of the heart with results of echocardiography during rest and during bicycle ergometry [correction of veloergometry] in 240 patients with ischemic heart disease, 60 patients with hypertensive disease and in 16 healthy persons. In some of the patients coronarography was carried out. It was established that the informative value of electrocardiography in assessment of the anatomo-functional state of the left ventricle depended on the contingent of the examined patients and reduces as disorders of the functional state of the myocardium tended to advance. The specificity and sensitivity of the electrocardiographic signs of left ventricular hypertrophy reduced in disturbances of ventricular conduction, presence of myocardial infarction in the anamnesis, increase of involvement of the cardiac arteries.

An assessment of left ventricular systolic function in pressure and volume overload heart with two shell compartment model of ellipsoid revolution.

Left ventricular (LV) midwall mechanics were evaluated in normal, pressure overload due to hypertension, and volume overload hearts due to aortic (AR) and mitral regurgitations (MR) using a 2 shell compartment model of ellipsoid revolution. While ejection fraction (EF) was in the normal range, midwall fractional shortening (MFS) was depressed with low end-diastolic and end-systolic stress in hypertrophied hearts with pressure overload. Not only LV volumes but also LV systolic pressure and wall thickness were increased in AR. LV end-diastolic pressure was elevated, and EF and MFS were reduced in patients with AR and congestive heart failure (CHF). In patients with MR and CHF, pulmonary capillary wedge pressure was elevated, LV volumes were enlarged and end-systolic stress was high, but LV wall thickness and MFS remained in the normal range. It is concluded from this observation that: 1) myocardial contractility is already depressed with normal systolic function in hypertrophied ventricle with pressure overload. 2) AR can be considered to be the disease of both pressure and volume overload, and symptoms of CHF are the result of depressed myocardial contractility. 3) MR is the disease of pure volume overload. Myocardial contractility is well preserved even with the presence of severe CHF in MR.

Assessment of relationship between the pattern of hypertrophy and the function of left ventricle in patients with chronic aortic regurgitation.

Pre- and postoperative echocardiograms of 64 patients with chronic aortic regurgitation who had undergone isolated aortic valvular replacement (AVR) were studied. These patients were divided into 3 groups as follows: (1) Group A patients who had preoperative end-diastolic radius to wall thickness ratio (R/Thd) less than or equal to 3. (2) Group B1 patients who had preoperative R/Thd greater than 3 and end-systolic radius to wall thickness ratio (R/Ths) less than 2. (3) Group B2 patients who had preoperative R/Thd greater than 3 and R/Ths greater than or equal to 2. Using this classification we assessed the relation between the pattern of hypertrophy and left ventricular (LV) function and the reversibility of LV dysfunction following AVR. Preoperatively, ejection fraction (EF) during handgrip exercise was unchanged in Group A (% delta EF: -2.8 +/- 7.1%) and significantly decreased in Groups B1 (-17.0 +/- 5.8%) and B2 (-20.2 +/- 4.6%). In the late postoperative period, however, it was, -1.2 +/- 3.3%, -2.0 +/- 4.6%, and -17.7 +/- 8.6% in Groups A, B1, B2, respectively. Preoperatively the slope of end-systolic wall stress/volume (ESWS-ESV relation was 1.96 +/- 0.43 in Group A (p less than 0.01 vs Group B2, NS vs Group B1), 1.54 +/- 0.38 in Group B1 (NS vs Group B2) and 1.17 +/- 0.47 in Group B2. It was stressed that a good relationship existed between the pattern of hypertrophy and function as well as the reversibility of LV dysfunction following AVR.