Regurgitation In Mitral Valve Prolapse Research Articles

Quantification of Mitral Regurgitation in Mitral Valve Prolapse by Three-Dimensional Vena Contracta Area: Derived Cutoff Values and Comparison With Two-Dimensional Multiparametric Approach

Echocardiographic grading of mitral regurgitation (MR) in mitral valve prolapse (MVP) is challenging. Three-dimensional (3D) vena contracta area (VCA) has been proposed as a valuable method. However, data defining the cutoff values of severity and validation in the subset of patients with MVP are scarce. The aim of this study was to validate the 3D VCA by 3D color-Doppler transesophageal echocardiography (TEE) in patients with MVP and to define the cutoff values of severity grading. The secondary aim was to compare 3D VCA to the effective regurgitant orifice area estimation by proximal isovelocity surface area (EROA-PISA) method. A total of 1,138 patients with at least moderate MR who underwent TEE were included. Three-dimensional VCA was measured, and the cutoff value and area under the curve (AUC) for the prediction of severe MR were estimated by receiver operating characteristic curve using a guideline-suggested multiparametric approach as the reference standard. In a subgroup of patients, 3D regurgitant volume (RV) and 3D fraction were calculated from mitral and left ventricular outflow tract stroke volumes to further validate 3D VCA against a 3D volumetric reference standard. The optimal 3D VCA cutoff value for predicting severe MR was 0.45cm2 (specificity, 0.87; sensitivity, 0.90) with an AUC of 0.95 using a multiparametric approach as reference. Three-dimensional VCA had a good linear correlation with EROA-PISA (r=0.62, P<.05) with larger values compared to EROA-PISA (0.63cm2 vs 0.44cm2, P<.05). A cutoff of 0.50cm2 (AUC of 0.84; sensitivity, 0.78; specificity, 0.78) predicts an EROA-PISA of 0.40cm2. Three-dimensional VCA had a good linear correlation with 3D RV (r=0.56, P<.01), with an AUC of 0.86 to predict a 3D fraction>50%. The present study suggests 0.45cm2 as the best cutoff value of 3D VCA to define severe MR in patients with MVP, showing an optimal agreement with the reference standard multiparametric approach and 3D RV.

Quantification of regurgitation in mitral valve prolapse with four-dimensional flow cardiovascular magnetic resonance

BackgroundFour-dimensional cardiovascular magnetic resonance (CMR) flow assessment (4D flow) allows to derive volumetric quantitative parameters in mitral regurgitation (MR) using retrospective valve tracking. However, prior studies have been conducted in functional MR or in patients with congenital heart disease, thus, data regarding the usefulness of 4D flow CMR in case of a valve pathology like mitral valve prolapse (MVP) are scarce. This study aimed to evaluate the clinical utility of cine-guided valve segmentation of 4D flow CMR in assessment of MR in MVP when compared to standardized routine CMR and transthoracic echocardiography (TTE).MethodsSix healthy subjects and 54 patients (55 ± 16 years; 47 men) with MVP were studied. TTE severity grading used a multiparametric approach resulting in mild/mild-moderate (n = 12), moderate-severe (n = 12), and severe MR (n = 30). Regurgitant volume (RVol) and regurgitant fraction (RF) were also derived using standard volumetric CMR and 4D flow CMR datasets with direct measurement of regurgitant flow (4DFdirect) and indirect calculation using the formula: mitral valve forward flow - left ventricular outflow tract stroke volume (4DFindirect).ResultsThere was moderate to strong correlation between methods (r = 0.59–0.84, p < 0.001), but TTE proximal isovelocity surface area (PISA) method showed higher RVol as compared with CMR techniques (PISA vs. CMR, mean difference of 15.8 ml [95% CI 9.9–21.6]; PISA vs. 4DFindirect, 17.2 ml [8.4–25.9]; PISA vs. 4DFdirect, 27.9 ml [19.1–36.8]; p < 0.001). Only indirect CMR methods (CMR vs. 4DFindirect) showed moderate to substantial agreement (Lin’s coefficient 0.92–0.97) without significant bias (mean bias 1.05 ± 26 ml [− 50 to 52], p = 0.757). Intra- and inter-observer reliability were good to excellent for all methods (ICC 0.87–0.99), but with numerically lower coefficient of variation for indirect CMR methods (2.5 to 12%).ConclusionsIn the assessment of patients with MR and MVP, cine-guided valve segmentation 4D flow CMR is feasible and comparable to standard CMR, but with lower RVol when TTE is used as reference. 4DFindirect quantification has higher intra- and inter-technique agreement than 4DFdirect quantification and might be used as an adjunctive technique for cross-checking MR quantification in MVP.

Quantification of regurgitation in mitral valve prolapse with automated real time echocardiographic 3D proximal isovelocity surface area: multimodality consistency and role of eccentricity index

Three-dimensional transthoracic echocardiography (3D-TTE) provides a semi-automated proximal isovelocity surface area method (3D-PISA) to obtain quantitative parameters. Data assessing regurgitation severity in mitral valve prolapse (MVP) are scarce, so we assessed the 3D-PISA method compared with 2D-PISA and cardiovascular magnetic resonance (CMR) and the role of an eccentricity index. We evaluated the 3D-PISA method for assessing MR in 54 patients with MVP (57 ± 14 years; 42 men; 12 mild/mild-moderate; 12 moderate-severe; and 30 severe MR). Role of an asymmetric (i.e. eccentricity index ≥ 1.25) flow convergence region (FCR) and inter-modality consistency were then assessed. 3D-PISA derived regurgitant volume (RVol) showed a good correlation with 2D-PISA and CMR derived parameters (r = 0.86 and r = 0.81, respectively). The small mean differences with 2D-PISA derived RVol did not reach statistical significance in overall population (5.7 ± 23 ml, 95% CI − 0.6 to 12; p = 0.08) but differed in those with asymmetric 3D-FCR (n = 21; 2D-PISA: 72 ± 36 ml vs. 3D-PISA: 93 ± 47 ml; p = 0.001). RVol mean values were higher using PISA methods (CMR 57 ± 33 ml; 2D-PISA 73 ± 39 ml; and 3D-PISA 79 ± 45 ml) and an overestimation was observed when CMR was used as reference (2D-PISA vs. CMR: mean difference: 15.8 ml [95% CI 10–22, p < 0.001]; and 3D-PISA vs. CMR: 21.5 ml [95% CI 14–29, p < 0.001]). Intra- and inter-observer reliability was excellent (ICC 0.91–0.99), but with numerically lower coefficient of variation for 3D-PISA (8%–10% vs. 2D-PISA: 12%–16%). 3D-PISA method for assessing regurgitation in MVP may enable analogous evaluation compared to standard 2D-PISA, but with overestimation in case of asymmetric FCR or when CMR is used as reference method.

The Average Pixel Intensity Method and Outcome of Mitral Regurgitation in Mitral Valve Prolapse

Mitral regurgitation (MR) is a frequent consequence of mitral valve prolapse (MVP). However, the echocardiographic grading of MR is challenging, and the recommended grading parameters have several limitations. The authors developed a novel echocardiographic parameter to grade MR, the average pixel intensity (API) method, on the basis of pixel intensity analysis of the continuous-wave Doppler signal. Transthoracic echocardiography was performed prospectively in consecutive patients with MVP (N=149). MR was quantitatively assessed using the API method, vena contracta width, effective regurgitant orifice area, and regurgitant volume. The primary clinical events were cardiovascular mortality, mitral valve surgery, percutaneous mitral intervention, and heart failure hospitalization. The API method was feasible in 90% of all patients with MVP, which was significantly higher than vena contracta width, effective regurgitant orifice area, and regurgitant volume. During a median follow-up period of 17months, 44 patients (32%) had major adverse cardiac events, and the majority of events occurred in the holosystolic MVP subgroup. The degree of MR severity by the API method was highly significant for the prediction of events. An API cutoff of 111 arbitrary units was defined as "severe" MR due to MVP, with overall superior sensitivity and specificity compared with cutoffs for established MR grading parameters. In patients who did not have major adverse cardiac events during the follow-up period (n=92), no significant changes in measures of MR severity were found on follow-up echocardiography. The API method is predictive of clinical events and outcomes in MR due to MVP. Therefore, the API method may be considered for grading the severity of MR due to MVP in clinical practice.

Grading of mitral regurgitation in mitral valve prolapse using the average pixel intensity method

AimsWe recently reported the feasibility of the average pixel intensity (API) method for grading mitral regurgitation (MR) in a heterogeneous MR population. Since mitral valve prolapse (MVP) is an important cause of primary MR, we more specifically investigated the feasibility of the API method and the MR flow dynamics in patients with MVP. MethodsTransthoracic echocardiography was performed by a single operator in consecutive MVP patients (n=112). MR was assessed using the API method, color Doppler, vena contracta width (VCW), effective regurgitant orifice area (PISA-EROA) and regurgitant volume (PISA-RV). ResultsThe API method was feasible in 89% of all MVP patients (68%, 71% for VCW and PISA method, respectively ;p<.001). Inter- and intra-observer correlations for API in MVP with non-holosystolic MR were 0.989 and 0.995. For the overall MVP-MR population, API had significant correlations with direct and indirect measures of MR severity. Based on ROC curves, an API cutoff value of 125 au was suggested to identify severe MR in MVP and a MR duration/systolic time ratio<100% (i.e. non-holosystolic MVP-MR) identifies patients with non-severe MR (API<125), whereas the majority of holosystolic MVP had severe MR (API>125). Finally, API analysis of the proto-, mid- and telesystolic phases of MR in MVP showed different kinetics in non-holosystolic compared to holosystolic MVP. ConclusionsThe API method is a feasible and reproducible method for grading MVP-MR. As the API method takes into account the temporal MR flow changes during the entire systolic cycle, it may be of added value in clinical practice.

The mechanisms, diagnosis and management of mitral regurgitation in mitral valve prolapse and hypertrophic cardiomyopathy.

Valvular disease is a frequent cardiac pathology leading to heart failure and, ultimately, death. Mitral regurgitation, defined as the inability of the two mitral leaflets to coapt, is a common valvular disease and a self sustained pathology. A better understanding of the mitral valve histological layers provides a better understanding of the leaflet and chordae changes in mitral valve prolapse. Mitral valve prolapse may occur in myxomatous degenerative abnormalities, connective tissue disorders or in sporadic isolated cases. It is the most common mitral abnormality of non-ischemic cause leading to severe surgery-requiring mitral regurgitation. In addition to standard echocardiographic investigations, newly implemented three-dimensional techniques are being used and they permit a better visualisation, from the so-called ‘surgical view’, and an improved evaluation of the mitral valve. Hypertrophic cardiomyopathy is the most frequent inherited myocardial disease caused by mutations in various genes encoding proteins of the cardiac sarcomere, leading to a marked left ventricular hypertrophy unexplained by other comorbidities. The pathological echocardiographic hallmarks of hypertrophic cardiomyopathy are left ventricular hypertrophy, left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. The systolic anterior motion of the mitral valve contributes to the development of mitral regurgitation and further narrows the left ventricular outflow tract, leading to more severe symptomatology. Cardiac magnetic resonance imaging accurately measures the left ventricular mass, the degree of diastolic function and it may also be used to distinguish phenotypic variants. The clinical outcome of patients with these pathologies is mostly determined by the selected option of treatment. The purpose of surgical correction regarding mitral valve involvement is to restore valvular competence. Surgery has proven to be the only useful treatment in preventing heart failure, improving symptomatology and reducing mortality. Our approach wishes to enhance the understanding of the mitral valve’s involvement in hypertrophic cardiomyopathy and mitral valve prolapse from genetic, haemodynamic and clinical perspectives, as well as to present novelties in the grand field of treatment.

Promoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients

Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that polymorphic variations in Matrix Metalloproteinase (MMP) genes might be predictors of left ventricular (LV) remodelling and severity of regurgitation in MVP. 70 MVP patients and 75 normal subjects were studied. We performed comprehensive echocardiography and analyzed promoter polymorphisms in the MMP-1 and MMP-3 genes. The MMP-3 -1612 5A/6A polymorphism showed strong associations with indices of mitral regurgitation and LV remodelling: Patients with 5A/5A allele had more pronounced remodelling and more severe mitral regurgitation than patients with the 6A/6A or 5A/6A alleles. We then cloned and sequenced 2 kb fragments of MMP-3 promoter from patients with 5A/5A and 6A/6A genotypes and found 4 different sets of promoter haplotypes. Promoter analysis showed that higher promoter activity was related to a more severe phenotype and that the haplotype variants had a more dominant role in determining the activity. Our data identifies the MMP-3 promoter haplotype as a novel marker of an adverse disease course in MVP, suggesting the presence of genetic determinants for the severity of MVP.

The Crossed Swords Sign: Insights into the Dilemma of Repair in Bileaflet Mitral Valve Prolapse

The need for bileaflet repair in bileaflet mitral valve prolapse (MVP) remains controversial. Will anterior leaflet prolapse resolve with posterior leaflet repair or should both leaflets be addressed? Single-leaflet MVP produces oppositely directed mitral regurgitant jets. Some patients show two crossed jets oppositely directed from the coaptation zone. We hypothesized that these indicate bileaflet lesions requiring complex repair. Echocardiograms and surgical reports of 52 consecutive patients with MVP undergoing surgery were reviewed. First, all 14 patients with two oppositely directed jets had prolapse of more than one leaflet. Each jet was related to discrete leaflet distortions causing malcoaptation. Six underwent valve replacement. Seven had both leaflets repaired. One had posterior leaflet repair and annuloplasty, with persistent mitral regurgitation requiring valve replacement. Second, 36 of 38 patients with single jets had single-leaflet MVP. One underwent replacement; all others did well with single-leaflet repair. Two patients with bileaflet MVP but only one jet did well with single-leaflet repair or annuloplasty. This crossed swords sign is an important clue to bileaflet mechanism of mitral regurgitation in MVP, associated with complex repair procedures. Thus, it provides a clue in the dilemma of bileaflet versus single-leaflet repair.

897 Assessment of regurgitation in mitral valve prolapse: vena contracta width vs. Doppler quantitative method compared with angiography

897 Assessment of regurgitation in mitral valve prolapse: vena contracta width vs. Doppler quantitative method compared with angiography

Exercise-induced regurgitation in mitral valve prolapse: Is it a new disease?

Exercise-induced regurgitation in mitral valve prolapse: Is it a new disease?

Exercise-Induced Mitral Regurgitation in Mitral Valve Prolapse

In patients with mitral valve prolapse (MVP), mitral regurgitation (MR) increases risk of valve replacement, endocarditis, and sudden death. This study examined the outcome of patients with MVP and no MR at rest who developed MR during exercise. Ninety-four subjects fulfilled entrance criteria and underwent supine bicycle exercise tests with echocardiographic evaluation every 2 to 3 minutes. …

Relation of Echocardiographic Morphology of the Mitral Apparatus to Mitral Regurgitation in Mitral Valve Prolapse: Assessment by Doppler Color Flow Imaging

Relation of Echocardiographic Morphology of the Mitral Apparatus to Mitral Regurgitation in Mitral Valve Prolapse: Assessment by Doppler Color Flow Imaging

Relation of echocardiographic morphology of the mitral apparatus to mitral regurgitation in mitral valve prolapse: Assessment by Doppler color flow imaging

Few data exist regarding the relationship of valvular anatomy and coaptation to the presence of mitral regurgitation (MR) in patients with mitral valve prolapse (MVP). Therefore this study was undertaken to assess the ability of two-dimensional echocardiographic features of mitral valve morphology to predict the presence, direction, and magnitude of MR as assessed by color Doppler flow imaging. MR was present in 21 of 46 patients with MVP on two-dimensional echocardiography. Echocardiograms were specifically evaluated for leaflet apposition, leaflet morphology, and mitral anulus diameter. Color flow images were analyzed for presence of MR, direction of the regurgitant jet, and area encompassing the largest jet visible in any view. Abnormal mitral leaflet coaptation on two-dimensional echocardiography was strongly associated with the presence of MR (p = 0.003), being present in 15 of 21 patients with as compared with 5 of 25 patients without MR. Similarly, mitral leaflet thickness and MR were closely associated (p = 0.0035), with the latter being present in 9 of 30 patients with normal and 12 of 16 patients with excessive leaflet thickness. MR jet direction tended to be anterior to central with posterior leaflet prolapse and posterior or central with anterior leaflet prolapse (p = 0.02). Maximal jet area of MR tended to be larger in patients with compared with those without mitral annular dilatation (5.4 +/- 2.3 versus 2.1 +/- 1.9 cm2, p = 0.001), and in those with abnormal rather than normal leaflet thickness (4.5 +/- 2.7 versus 2.0 +/- 1.6 cm2, p = 0.009). Thus the presence, direction, and size of MR jets in MVP are related to structural abnormality of the mitral apparatus on echocardiography.

The spectrum of mitral regurgitation in idiopathic mitral valve prolapse: a Color Doppler study

To characterize the spectrum of mitral regurgitation in mitral valve prolapse, one hundred patients were studied by color Doppler flow mapping. The findings were correlated with the clinical presentation and with the possible complications. Mitral regurgitation was absent in 46 patients, mild in 26 patients, moderate in 18 patients and severe in 10 patients. The jet orientation was central in 15 patients, antero-medial in 13 patients and postero-lateral in 26 patients. The regurgitation was early systolic in 7 patients, late systolic in 20 patients and holosystolic in 27 patients. A good agreement was observed between the color flow patterns and the presence, timing and radiation of a murmur. Systolic clicks were not predictors of the presence or the severity of regurgitation. The grade of mitral regurgitation was positively correlated with, age, left heart enlargement and valvular redundancy. No sex difference was observed. The prevalence of serious arrhythmias or cerebral ischemic events was not significantly increased when a regurgitation was present.

Temporal resolution of mitral regurgitation in patients with mitral valve prolapse: A phonocardiographic and doppler echocardiographic study

To assess the timing and duration of mitral regurgitation in mitral valve prolapse, 20 patients with a mid-systolic click or late systolic murmur, or both (Group 1) and 16 patients with a pansystolic murmur with late systolic accentuation (Group 2) were studied with phonocardiography and echocardiography including various Doppler techniques. The subjects' ages ranged from 15 to 73 years.Mitral valve prolapse with mitral regurgitation was observed in 15 of 20 patients in Group 1 and in all 16 patients in Group 2. M-mode Doppler color echocardiography demonstrated a mitral regurgitant signal throughout systole and isovolumic relaxation in all but 1 of these 31 patients regardless of the pattern of the systolic murmur. The regurgitant signal was recorded after the click in only one patient with mitral valve prolapse in Group 1. Two of the five patients in Group 1 without two-dimensional echocardiographic findings of mitral valve prolapse had the early systolic signal of mitral regurgitation. The timing and duration of the mitral regurgitant signal detected in patients in Group 1 with pulsed or continuous wave Doppler ultrasound varied with the site of the sample volume or beam direction. In the patients in Group 2, however, the signal was demonstrated throughout systole and isovolumic relaxation by both Doppler methods. Compared with M-mode Doppler color echocardiography, therefore, pulsed and continuous wave Doppler methods were less sensitive and thus inadequate to investigate the timing and duration of mitral regurgitation in mitral valve prolapse, especially in patients with a mid-systolic click or a late systolic murmur, or both, who had mild or eccentric mitral regurgitant jets.In conclusion, 1) mitral regurgitation is frequently present throughout systole and isovolumic relaxation in patients with mitral valve prolapse; 2) pulsed and continuous wave Doppler techniques are of limited value in assessing the timing and duration of mitral regurgitation in such patients; and 3) M-mode Doppler color echocardiography is more useful in the temporal resolution of mitral regurgitation in these patients.

Value and limitations of color Doppler flow mapping in the detection and semiquantification of valvular regurgitation.

We compared color Doppler flow mapping data to angiographic data in 294 patients with suspected valvular regurgitation. Thirty-one patients had rheumatic mitral regurgitation and 37 had mitral regurgitation due to mitral valve prolapse by angiography. Ten patients had no angiographic regurgitation (4 rheumatic, 6 prolapse). The remaining patients included 86 with suspected aortic regurgitation and 130 with suspected tricuspid regurgitation. Angiographically 74 had aortic regurgitation and 111 tricuspid regurgitation. The maximum size of regurgitant jets was evaluated in each patient by color flow mapping. The width of the jets was also taken into consideration. In 29 of the 31 with rheumatic regurgitation and 67 of the 74 with aortic regurgitation by angiography, abnormal regurgitant signals were detected by color flow mapping. In both rheumatic mitral regurgitation and aortic regurgitation, color Doppler estimation of the jets correlated well with angiographic grading. The regurgitant jets in these regurgitation were not eccentric. In the 37 with mitral regurgitation in mitral valve prolapse by left ventriculography, abnormal jets were detected in 35 by color flow mapping. However, the regurgitant jets were eccentric and color Doppler estimation of the jets correlated poorly with angiographic grading. In patients with tricuspid regurgitation, color Doppler grading of regurgitation correlated poorly with right ventriculographic grading. A color Doppler underestimation was observed in 48%. In conclusion, color Doppler flow mapping is useful in the noninvasive detection and semiquantification of rheumatic mitral regurgitation and aortic regurgitation having non-eccentric jets, although this technique often underestimates the severity of regurgitation in mitral valve prolapse.

Mechanisms of severe mitral regurgitation in mitral valve prolapse determined from analysis of operatively excised valves

Certain clinical and mitral valvular morphologic findings are described in 83 patients (age 26 to 79 years [mean, 60]; 26 women [31%] and 57 men [69%]) with mitral valve prolapse (MVP) and mitral regurgitation (MR) severe enough to warrant mitral valve replacement. All 83 operatively excised valves were examined by the same person, and all excised valves had been purely regurgitant (no element of stenosis). No patients had hemodynamic evidence of dysfunction of the aortic valve. In each valve a portion of the posterior mitral leaflet was elongated such that the distance from the distal margin to basal attachment of this leaflet was similar to the distance from the distal margin of the anterior leaflet to its basal attachment to the left atrial wall. Two major mechanisms for the severe MR were found: (1) dilatation of the mitral anulus with or without rupture of chordae tendineae and (2) rupture of chordae tendineae with or without dilatation of the mitral anulus. Of the 83 patients, 48 (58%) had both dilated anuli (> 11 cm in circumference) and ruptured chordae tendineae; 16 (19%) had dilated anuli without ruptured chrodae, and 16 (19%) had ruptured chordae without significant anular dilatation. In three patients the anulus was not dilated, nor were chordae ruptured, and therefore the mechanism of the MR is uncertain. Mitral chordal rupture was nearly as frequent in the 64 patients with clearly dilated anular circumferences as in the 19 patients with normal or insignificantly dliated anular circumferences (≤ 11 cm).

Evidence for progression from mild to severe mitral regurgitation in mitral valve prolapse

Little information is available concerning the progression of mild to severe mitral regurgitation (MR) in patients with mitral valve prolapse (MVP). This study reports 86 patients, average age 60 years, who presented with cardiac symptoms, precordial systolic murmur, severe MR and a high incidence of MVP on echocardiography (57 of 75 [75%]) and left ventriculography (61 of 84 [73%]). Seventy-five surgically excised mitral valves appeared grossly enlarged and floppy. Histologic studies showed extensive myxomatous changes throughout the leaflets and chordae. Eighty patients had had precordial murmurs first described at average age 34 years, but the average age at which symptoms of cardiac dysfunction appeared was 59. However, once symptoms developed, mitral valve surgery was required within 1 year in 67 of 76 patients who had undergone surgery. Atrial fibrillation, present in 48 of 86 patients (56%), or ruptured chordae tendineae, present in 39 of 76 patients (51%), may have contributed to this rapid progression and deterioration. Additionally, 13 patients had a remote history of documented infective endocarditis. Twenty-eight patients had at least 1 type of serial clinical evaluation that indicated progressive MR in all 28 patients on the basis of changing auscultatory findings (24 of 26), progressive radiographic cardiomegaly (24 of 25), echocardiographic left atrial enlargement (4.3 to 5 cm in 11 patients) and angiographically worsening MR (14 of 15). Twenty-four of these patients had evidence of MVP on at least 1 of their initial studies. Thus, mild MR due to MVP and myxomatous mitral valves is a progressive disease in some patients with MVP.

Mitral regurgitation in mitral valve prolapse: Detection by pulsed doppler echocardiography versus angiography and cardiac auscultation. Correlation with cardiac arrhythmias by ambulatory monitoring

Mitral regurgitation in mitral valve prolapse: Detection by pulsed doppler echocardiography versus angiography and cardiac auscultation. Correlation with cardiac arrhythmias by ambulatory monitoring