On Blurry Boundaries When Defining Digital Biomarkers: How Much Biology Needs to Be in a Digital Biomarker?

Recent years have seen a rise in research where so called "digital biomarkers" represent the focal study interest. Many researchers understand that digital biomarkers describe digital footprints providing insights into healthy and pathological human (neuro-)biology. Beyond that the term digital biomarker is also used at times to describe more general concepts such as linking digital footprints to human behavior (which itself can be described as the result of a biological system). Given the lack of consensus on how to define a digital biomarker, the present short mini-review provides i) an overview on various definitions and ii) distinguishes between direct (narrow) or indirect (broad) concepts of digital biomarkers. From our perspective, digital biomarkers meant as a more direct (or narrow) concept describe digital footprints being directly linked to biological variables, such as stemming from molecular genetics, epigenetics, endocrinology, immunology or brain imaging, to name a few. More indirect concepts of digital biomarkers encompass digital footprints being linked to human behavior that may act as latent variables indirectly linked to biological variables.

The AURORA Study: a longitudinal, multimodal library of brain biology and function after traumatic stress exposure.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

Digital biomarkers of cognitive function.

To identify digital biomarkers associated with cognitive function, we analyzed human-computer interaction from 7 days of smartphone use in 27 subjects (ages 18-34) who received a gold standard neuropsychological assessment. For several neuropsychological constructs (working memory, memory, executive function, language, and intelligence), we found a family of digital biomarkers that predicted test scores with high correlations (p < 10-4). These preliminary results suggest that passive measures from smartphone use could be a continuous ecological surrogate for laboratory-based neuropsychological assessment.

Data mining for health: staking out the ethical territory of digital phenotyping.

Digital phenotyping uses smartphone and wearable signals to measure cognition, mood, and behavior. This promising new approach has been developed as an objective, passive assessment tool for the diagnosis and treatment of mental illness. Digital phenotyping is currently used with informed consent in research studies but is expected to expand to broader uses in healthcare and direct-to-consumer applications. Digital phenotyping could involve the collection of massive amounts of individual data and potential creation of new categories of health and risk assessment data. Because existing ethical and regulatory frameworks for the provision of mental healthcare do not clearly apply to digital phenotyping, it is critical to consider its possible ethical, legal, and social implications. This paper addresses four major areas where guidelines and best practices will be helpful: transparency, informed consent, privacy, and accountability. It will be important to consider these issues early in the development of this new approach so that its promise is not limited by harmful effects or unintended consequences.

The ENGAGE study: Integrating neuroimaging, virtual reality and smartphone sensing to understand self-regulation for managing depression and obesity in a precision medicine model.

Precision medicine models for personalizing achieving sustained behavior change are largely outside of current clinical practice. Yet, changing self-regulatory behaviors is fundamental to the self-management of complex lifestyle-related chronic conditions such as depression and obesity - two top contributors to the global burden of disease and disability. To optimize treatments and address these burdens, behavior change and self-regulation must be better understood in relation to their neurobiological underpinnings. Here, we present the conceptual framework and protocol for a novel study, "Engaging self-regulation targets to understand the mechanisms of behavior change and improve mood and weight outcomes (ENGAGE)". The ENGAGE study integrates neuroscience with behavioral science to better understand the self-regulation related mechanisms of behavior change for improving mood and weight outcomes among adults with comorbid depression and obesity. We collect assays of three self-regulation targets (emotion, cognition, and self-reflection) in multiple settings: neuroimaging and behavioral lab-based measures, virtual reality, and passive smartphone sampling. By connecting human neuroscience and behavioral science in this manner within the ENGAGE study, we develop a prototype for elucidating the underlying self-regulation mechanisms of behavior change outcomes and their application in optimizing intervention strategies for multiple chronic diseases.

Aortic root dynamics and surgery: from craft to science.

Since the fifteenth century beginning with Leonardo da Vinci's studies, the precise structure and functional dynamics of the aortic root throughout the cardiac cycle continues to elude investigators. The last five decades of experimental work have contributed substantially to our current understanding of aortic root dynamics. In this article, we review and summarize the relevant structural analyses, using radiopaque markers and sonomicrometric crystals, concerning aortic root three-dimensional deformations and describe aortic root dynamics in detail throughout the cardiac cycle. We then compare data between different studies and discuss the mechanisms responsible for the modes of aortic root deformation, including the haemodynamics, anatomical and temporal determinants of those deformations. These modes of aortic root deformation are closely coupled to maximize ejection, optimize transvalvular ejection haemodynamics and-perhaps most importantly-reduce stress on the aortic valve cusps by optimal diastolic load sharing and minimizing transvalvular turbulence throughout the cardiac cycle. This more comprehensive understanding of aortic root mechanics and physiology will contribute to improved medical and surgical treatment methods, enhanced therapeutic decision making and better post-intervention care of patients. With a better understanding of aortic root physiology, future research on aortic valve repair and replacement should take into account the integrated structural and functional asymmetry of aortic root dynamics to minimize stress on the aortic cusps in order to prevent premature structural valve deterioration.

Tenting volume: three-dimensional assessment of geometric perturbations in functional mitral regurgitation and implications for surgical repair.

BACKGROUND AND AIM OF THE STUDY: Functional mitral regurgitation (FMR) often complicates dilated cardiomyopathy (DCM), and portends a poor prognosis. Debate over the optimal treatment continues, underscoring the present incomplete understanding of the patho-anatomic mechanisms of this disease. Studies of mitral tenting volume and tenting area, and echocardiographic measures of abnormal apical systolic leaflet geometry have linked mitral leaflet deformation with subvalvular left ventricular (LV) remodeling in chronic ischemic MR. The relative contributions of annular versus subvalvular remodeling in FMR due to DCM are less clear. Here, the validity of 3-D measurement of mitral deformation, tenting volume, as a correlate of MR in DCM, was tested. The ability of annular and subvalvular remodeling to predict mitral deformation was then determined. METHODS: Eight sheep underwent placement of radiopaque markers on the mitral annulus and leaflets. Global LV, annular and subvalvular geometry, as well as mitral tenting height, area and volume were calculated before (Control) and after the development of pacing-induced cardiomyopathy and MR (DCM). Multivariable regression determined which measure of mitral deformation was the best predictor of MR. Regression analysis was also used to find geometric predictors of mitral tenting volume. RESULTS: In a multivariable analysis, mitral tenting volume was the only independent predictor of severity of MR (r(2) = 0.79, standard error of estimate (SEE) = 0.58). Increased tenting volume correlated best with increased mitral annular septal-lateral diameter (r(2) = 0.67, SEE = 0.72). CONCLUSION: The 3-D tenting volume correlates best with severity of FMR. Mitral deformation (increased tenting volume) observed in DCM is predicted by annular dilation, but not by subvalvular LV remodeling. These data support the use of an undersized annuloplasty in DCM complicated by FMR, and may guide the rational design of new therapies for this vexing disease.

Left ventricular volume shifts and aortic root expansion during isovolumic contraction.

BACKGROUND AND AIM OF THE STUDY: Aortic valve opening involves conformational changes of the aortic root, including the ventricular-aortic junction (VAJ), sinotubular junction (STJ), and cusps. Moreover, the aortic root is contiguous with the left ventricular outflow tract (LVOT), which changes diameter throughout the cardiac cycle. Aortic root expansion prior to valve opening facilitates outward displacement of aortic cusp attachments, which helps flatten the cusps, thereby reducing cusp stress and fatigue, ultimately enhancing functional valve durability. The mechanisms underlying aortic root expansion prior to valve opening, however, remain incompletely characterized. The study aim was to establish a link between such aortic root expansion and intraventricular volume shifts into the LVOT during isovolumic contraction (IVC). METHODS: Miniature radiopaque markers were implanted on the left ventricle, VAJ, STJ, and aortic cusps of six sheep. After one week, 3-D marker coordinates were obtained using biplane videofluoroscopy (60 Hz). Triangular areas at the VAJ and STJ were calculated; LV main chamber (non-LVOT) and LVOT volumes were calculated using multiple tetrahedra. End-diastole was defined as the peak of the electrocardiogram R-wave, and end-IVC when aortic cusp separation began. RESULTS: During IVC, blood within the left ventricle was redistributed to the LVOT: mean LVOT volume was increased (+0.2 +/- 0.1 ml, p = 0.009) as non-LVOT volume fell (-0.8 +/- 0.4 ml, p = 0.006). Concomitantly, the aortic root expanded as both VAJ and STJ areas increased (+0.23 +/- 0.12 cm2 (p = 0.005) and +0.25 +/- 0.14 cm2 (p = 0.007), respectively) prior to aortic cusp separation. CONCLUSION: Aortic root expansion prior to valve opening is closely related to intraventricular volume shifts into the LVOT during IVC. Such volume shifts may 'prime' the aortic valve for ejection. These findings expand our understanding of cardiac dynamics by showing that blood acts as a coupling link between various cardiac units. Preservation of these normal aortic root dynamics may enhance the efficacy and durability of aortic surgical interventions.

Mitral leaflet remodeling in dilated cardiomyopathy.

BACKGROUND: Normal mammalian mitral leaflets have regional heterogeneity of biochemical composition, collagen fiber orientation, and geometric deformation. How leaflet shape and regional geometry are affected in dilated cardiomyopathy is unknown. METHODS AND RESULTS: Nine sheep had 8 radio-opaque markers affixed to the mitral annulus (MA), 4 markers sewn on the central meridian of the anterior mitral leaflet (AML) forming 4 distinct segments S1 to S4 and 2 on the posterior leaflet (PML) forming 2 distinct segments S5 and S6. Biplane videofluoroscopy and echocardiography were performed before and after rapid pacing (180 to 230 bpm for 15+/-6 days) sufficient to develop tachycardia-induced cardiomyopathy (TIC) and functional mitral regurgitation (FMR). Leaflet tethering was defined as change of displacement of AML and PML edge markers from the MA plane from baseline values while leaflet length was obtained by summing the segments between respective leaflet markers. With TIC, total AML and PML length increased significantly (2.11+/-0.16 versus 2.43+/-0.23 cm and 1.14+/-0.27 versus 1.33+/-0.25 cm before and after pacing for AML and PML, respectively; P<0.05 for both), but only segments near the edge of each leaflet (S4 lengthened by 23+/-17% and S5 by 24+/-18%; P<0.05 for both) had significant regional remodeling. AML shape did not change and no leaflet tethering was observed. CONCLUSIONS: TIC was not associated with leaflet tethering or shape change, but both anterior and posterior leaflets lengthened because of significant remodeling localized near the leaflet edge. Leaflet remodeling accompanies mitral regurgitation in cardiomyopathy and casts doubt on FMR being purely "functional" in etiology.

Ablation of mitral annular and leaflet muscle: effects on annular and leaflet dynamics.

Mitral annular (MA) and leaflet three-dimensional (3-D) dynamics were examined after circumferential phenol ablation of the MA and anterior mitral leaflet (AML) muscle. Radiopaque markers were sutured to the left ventricle, MA, and both mitral leaflets in 18 sheep. In 10 sheep, phenol was applied circumferentially to the atrial surface of the mitral annulus and the hinge region of the AML, whereas 8 sheep served as controls. Animals were studied with biplane video fluoroscopy for computation of 3-D mitral annular area (MAA) and leaflet shape. MAA contraction (MAACont) was determined from maximum to minimum value. Presystolic MAA (PS-MAACont) reduction was calculated as the percentage of total reduction occurring before end diastole. Phenol ablation decreased PS-MAACont (72 +/- 6 vs. 47 +/- 31%, P = 0.04) and delayed valve closure (31 +/- 11 vs. 57 +/- 25 ms, P = 0.017). In control, the AML had a compound sigmoid shape; after phenol, this shape was entirely concave to the atrium during valve closure. These data indicate that myocardial fibers on the atrial side of the valve influence the 3-D dynamic geometry and shape of the MA and AML.

Influence of anterior mitral leaflet second-order chordae tendineae on left ventricular systolic function.

BACKGROUND: The contribution of anterior mitral leaflet second-order ("strut") chordae tendineae to left ventricular (LV) systolic mechanics is debated; we measured the in vivo contribution of anterior chordae tendineae (ACT) and posterior chordae tendineae (PCT) to regional and global LV contractile function. METHODS AND RESULTS: Eight sheep had radiopaque markers implanted in the LV epicardium, partitioning the ventricle into 12 regions. Microminiature force transducers and snares were sutured to anterior leaflet "strut" chordae originating from ACT and PCT papillary muscles. Chordal tension, marker images, and hemodynamic data were acquired before and after (CUT) severing ACT and PCT. Fractional area shrinkage and slope of the regional end-diastolic area-regional stroke work relation (r-PRSW) were computed for each LV region. CUT did not affect global LV systolic function but reduced FAS in LV segments near the PCT insertion site: equatorial posterior lateral (19+/-2% versus 16+/-2%, P<0.05), apical posterior lateral (23+/-4% versus 19+/-4%, P<0.05), and posterior medial LV segments (16+/-2% versus 13+/-2%, P<0.05). r-PRSW fell near both the ACT (equatorial anterior medial [84+/-8 versus 62+/-11 mm Hg, P<0.05] and lateral [73+/-7 versus 53+/-9 mm Hg, P<0.05]) and PCT (apical posterior medial [91+/-12 versus 67+/-17 mm Hg, P<0.05] and lateral [72+/-8 versus 59+/-9 mm Hg, P<0.05]) LV insertion sites. Maximum tension in PCT was higher than in ACT (0.81+/-0.1 versus 0.52+/-0.08N, P<0.01). CONCLUSIONS: Dividing anterior leaflet strut chordae in sheep was associated acutely with regional LV systolic dysfunction near the chordal insertion sites. Caution is necessary when embarking on procedures that cut second-order chordae to treat ischemic mitral regurgitation, since this may compromise LV systolic function in ventricles that are already impaired.

Alterations in left ventricular curvature and principal strains in dilated cardiomyopathy with functional mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: Functional mitral regurgitation (FMR) is increasingly recognized as a left ventricular (LV) disease. Dilated cardiomyopathy (DCM) is commonly accompanied by FMR and reduction of LV torsion. Therapeutic targets for DCM include LV size reduction, altered LV shape, elimination of MR, and increasing LV torsion. It was hypothesized that, in addition to increasing LV size, DCM with FMR would alter normal LV shape and reduce and alter the direction of principal strains across the LV wall. This hypothesis was tested by measuring changes in epicardial and endocardial 2-D principal strains and regional radii of curvature accompanying tachycardia-induced cardiomyopathy in ovine hearts. METHODS: Radio-opaque marker arrays were implanted into the left ventricle of eight sheep, including one subepicardial triangle and one subendocardial triangle in the anterior wall of the left ventricle. At one week postoperatively, biplane videofluoroscopy was used to determine marker dynamics. Rapid ventricular pacing was then instituted until FMR and signs of heart failure developed, and fluoroscopy was repeated. Circumferential LV radii of curvature were determined from marker triplets. RESULTS: DCM changed the normal epicardial oval LV cross-section to a more circular configuration. The endocardium maintained its normal circular shape as the left ventricle dilated. Deformations of the triangles from end-diastole to end-systole were determined, and the magnitude and direction of 2-D principal strains calculated. DCM was associated with decreased magnitude of both epicardial (-0.095 +/- 0.055 versus -0.040 +/- 0.032, p = 0.006) and endocardial (-0.117 +/- 0.047 versus -0.073 +/- 0.037, p = 0.023) principal strains. DCM reduced the angle of epicardial but not endocardial principal strain. CONCLUSION: DCM with FMR is associated with LV dilation, circularization of the normally oval equatorial circumferential LV epicardium, transmural reduction in principal strain, and decrease in angle of principal epicardial strain. These changes contribute to a reduction in the net torsional moment and may guide the development of reverse remodeling procedures for the dilated, failing ventricle with FMR.

Ischemia in three left ventricular regions: Insights into the pathogenesis of acute ischemic mitral regurgitation.

BACKGROUND: Acute posterolateral left ventricular ischemia in sheep results in ischemic mitral regurgitation, but the effects of ischemia in other left ventricular regions on ischemic mitral regurgitation is unknown. METHODS: Six adult sheep had radiopaque markers placed on the left ventricle, mitral annulus, and anterior and posterior mitral leaflets at the valve center and near the anterior and posterior commissures. After 6 to 8 days, animals were studied with biplane videofluoroscopy and transesophageal echocardiography before and during sequential balloon occlusion of the left anterior descending, distal left circumflex, and proximal left circumflex coronary arteries. Time of valve closure was defined as the time when the distance between leaflet edge markers reached its minimum plateau, and systolic leaflet edge separation distance was calculated on the basis of left ventricular ejection. RESULTS: Only proximal left circumflex coronary artery occlusion resulted in ischemic mitral regurgitation, which was central and holosystolic. Delayed valve closure (anterior commissure, 58 +/- 29 vs 92 +/- 24 ms; valve center, 52 +/- 26 vs 92 +/- 23 ms; posterior commissure, 60 +/- 30 vs 94 +/- 14 ms; all P <.05) and increased leaflet edge separation distance during ejection (mean increase, 2.2 +/- 1.5 mm, 2.1 +/- 1.9 mm, and 2.1 +/- 1.5 mm at the anterior commissure, valve center, and posterior commissure, respectively; P <.05 for all) was seen during proximal left circumflex coronary artery occlusion but not during left anterior descending or distal left circumflex coronary artery occlusion. Ischemic mitral regurgitation was associated with a 19% +/- 10% increase in mitral annular area, and displacement of both papillary muscle tips away from the septal annulus at end systole. CONCLUSIONS: Acute ischemic mitral regurgitation in sheep occurred only after proximal left circumflex coronary artery occlusion along with delayed valve closure in early systole and increased leaflet edge separation throughout ejection in all 3 leaflet coaptation sites. The degree of left ventricular systolic dysfunction induced did not correlate with ischemic mitral regurgitation, but both altered valvular and subvalvular 3-dimensional geometry were necessary to produce ischemic mitral regurgitation during acute left ventricular ischemia.

Tachycardia-induced cardiomyopathy in the ovine heart: mitral annular dynamic three-dimensional geometry.

BACKGROUND: Ring annuloplasty has been used to correct annular dilatation and mitral regurgitation in dilated cardiomyopathy, but little is known about the dynamic precise 3-dimensional geometry of the mitral annulus in this condition. METHODS: Nine sheep had radiopaque markers sewn to the mitral annulus, creating 8 distinct segments beginning at the posterior commissure (segments 1-4, septal mitral annulus; segments 5-8, lateral mitral annulus). Biplane videofluoroscopy and transesophageal echocardiography were performed before and after rapid pacing (180-230 min(-1) for 15 +/- 6 days) sufficient to develop tachycardia-induced cardiomyopathy and mitral regurgitation. Mitral annular segment contraction was defined as the percentage difference between maximum and minimum lengths. Mitral annular area and mitral annular septal-lateral and commissure-commissure diameters and 3-dimensional shape were determined from marker coordinates. RESULTS: With tachycardia-induced cardiomyopathy, end-diastolic mitral annular area, septal-lateral diameter, and commissure-commissure diameter increased by 36% +/- 14%, 25% +/- 12%, and 9% +/- 5%, respectively (P <.01), whereas mitral regurgitation increased from 0.3 +/- 0.2 to 2.2 +/- 0.9 (P <.0001). All annular segments dilated at end-diastole with tachycardia-induced cardiomyopathy, except the segment between the midseptal annulus and the left fibrous trigone. Annular segment contraction was significantly decreased with tachycardia-induced cardiomyopathy in the lateral, but not in the septal, regions. Three-dimensional reconstruction of annular shape revealed a saddle shape of the annulus at baseline; this shape was also measured with tachycardia-induced cardiomyopathy, but there was some flattening of the septal annulus. CONCLUSIONS: With tachycardia-induced cardiomyopathy, the mitral annulus dilated substantially, being more in the septal-lateral than in the commissure-commissure dimension. Greater annular segmental dilatation and decreased contraction occurred in the lateral annulus. The saddle shape of the annulus was retained but flattened.

Atrial contraction and mitral annular dynamics during acute left atrial and ventricular ischemia in sheep.

In six sheep, radiopaque markers were placed on the left ventricle (LV), the mitral annulus, the left atrium (LA), and the central edge of both mitral leaflets to investigate the effects of acute LV ischemia on atrial contraction, mitral annular area (MAA), and mitral regurgitation (MR). Animals were studied with biplane videofluoroscopy and transesophageal echocardiography before and during balloon occlusion of the left anterior descending (LAD), distal circumflex (dLCX), and proximal circumflex (pLCX) coronary arteries. MAA and LA area were calculated from the corresponding markers. LAD occlusion did not alter LA area reduction or presystolic MAA reduction, whereas dLCX occlusion resulted in a mild decrease in the former with no change in the latter. Neither occlusion resulted in MR. pLCX occlusion, however, significantly decreased LA area and presystolic MAA reduction and resulted in increased end-diastolic MAA, delayed valve closure from end diastole, and MR. Decreased atrial contractile function, as observed during acute posterolateral ischemia, is linked to diminished presystolic mitral annular reduction, a larger mitral annular size at end diastole, and MR.

Annular versus subvalvular approaches to acute ischemic mitral regurgitation.

BACKGROUND: Ischemic mitral regurgitation (IMR) has been attributed to annular dilatation, papillary muscle (PM) displacement ("apical leaflet tenting"), or both. We compared the efficacy of reducing annular or subvalvular dimensions to gain more mechanistic insight into acute IMR. METHODS: Eight adult sheep underwent implantation of radiopaque markers on the LV, mitral annulus (MA), each leaflet edge, and each PM tip. Trans-annular septal-lateral (SL) and inter-PM tip sutures were placed and externalized. Biplane videofluoroscopy and transesophageal echocardiography were performed before and continuously during LCx occlusion-induced IMR with SL annular (SLAC) or inter-PM (PAPS) suture tightening (4 to 5 mm of cinching for 5 seconds during ischemia). MA SL dimension, inter-papillary distance (APM-PPM), and the distances between the anterior (APM) and posterior (PPM) PM tips and the mid-septal annulus ("saddle horn") were calculated from 3-D marker coordinates at end-systole. RESULTS: SLAC reduced IMR (grade=2.1+/-0.6 versus 0.7+/-0.5, P.001), SL annular diameter (4.9+/-2.5 mm smaller versus pre-cinching; P.001), and PM-"saddle horn" distances (0.9+/-0.7 and 1.0+/-0.8 mm reduction for APM and PPM, respectively; P.005). PAPS reduced APM-PPM distance (3.7+/-1.8 mm reduction versus precinching; P.001), only slightly decreased the PPM-"saddle horn" distance (0.3+/-0.3 mm reduction; P.03), and had no effect on IMR. CONCLUSIONS: Acute IMR was abolished by annular SL reduction, which also repositioned both PM tips closer to the mid-septal annulus and paradoxically increased leaflet "apical tenting"; reducing inter-papillary dimension was not effective, even though it displaced the leaflets toward the annular plane (less "apical tenting").

Will a partial posterior annuloplasty ring prevent acute ischemic mitral regurgitation?

BACKGROUND: Acute posterolateral ischemia in sheep results in ischemic mitral regurgitation (IMR). While complete ring annuloplasty prevents acute IMR, partial annuloplasty rings may offer a more physiologic repair, but are untested in animal models of IMR. METHODS: Radiopaque markers were placed on the LV, mitral annulus (MA), and leaflets in 13 sheep. Seven sheep served as controls, and 6 had a St. Jude Tailor partial flexible ring implanted (29 mm in 5, 31 mm in 1). After 8+/-1 day, the animals were studied with biplane videofluoroscopy and echocardiography before and during acute posterolateral LV ischemia (balloon occlusion of circumflex artery). Mitral annular area (MAA), septal-lateral annular diameter (SL), annular perimeters, and leaflet edge separation were calculated from 3-D marker coordinates. RESULTS: The average degree of mitral regurgitation increased from 0.0+/-0.0 to 2.1+/-0.7 (P=0.0006) in the control group during acute ischemia but remained unchanged in the Tailor group (0.1+/-0.2 for both conditions). The change in MAA throughout the cardiac cycle before ischemia was 17+/-4% in control animals, but only 5+/-2% (P=0.0002) in the Tailor ring group. Unlike the control animals, there was no increase in MAA (5.4+/-0.8 and 5.5+/-0.7 cm(2), respectively; p=NS) nor dilatation of the muscular annulus (6.2+/-0.3 and 6.2+/-0.4, respectively; p=NS) during ischemia with the Tailor ring. Mitral SL dimension increased slightly with ischemia (2.3+/-0.2 versus 2.2+/-0.2 cm, P=0.03). Although posterior leaflet motion was limited, as observed with complete rings, normal annular flexion was maintained with the Tailor ring before and during acute ischemia. CONCLUSIONS: The Tailor partial annuloplasty ring prevented acute IMR probably by limiting SL diameter dilatation during acute ischemia. In this animal model of acute IMR, a partial, flexible posterior annuloplasty ring is as effective as a complete ring.

Mechanistic insights into posterior mitral leaflet inter-scallop malcoaptation during acute ischemic mitral regurgitation.

BACKGROUND: Three-dimensional dynamics of the 3 individual scallops within the posterior mitral leaflet during acute ischemic mitral regurgitations have not been previously measured. METHODS: Radiopaque markers were sutured to the mitral annulus, papillary muscle tips, and leaflet edges in 13 sheep. Immediately postoperatively, under open-chest conditions, 3-D marker coordinates were obtained using high-speed biplane videofluoroscopy before and during echocardiographically verified acute ischemic mitral regurgitation produced by occlusion of the left circumflex coronary artery. RESULTS: During acute ischemic mitral regurgitation, at end systole, the anterolateral edge of the central scallop was displaced 0.8+/-0.9 mm laterally and 0.9+/-0.6 mm apically away from the anterolateral scallop; such displacement correlated with lateral displacement of the lateral annulus (R(2)=0.7, SEE=0.7 mm, P<0.001) and movement of the right lateral annulus away from the nonischemic anterior papillary tip (R(2)=0.6, SEE=0.8 mm, P=0.002), respectively. End-systolic displacement of the posteromedial edge of the central scallop was 1.4+/-0.9 mm anteriorly and 0.9+/-0.6 mm laterally away from the posteromedial scallop, corresponding to anterior displacement of the mid-lateral annulus (R(2)=0.5, SEE=1.0 mm, P<0.001). CONCLUSIONS: Malcoaptation of the scallops within the posterior leaflet during acute left ventricular ischemia is a novel observation. The primary geometric mechanism underlying scallop malcoaptation in acute ischemic mitral regurgitation was annular dilatation, which hindered leaflet coaptation by drawing the individual scallops apart. These findings support the use of annular reduction in the repair of ischemic mitral regurgitation and also suture closure of prominent subcommissures between posterior leaflet scallops.

Hemodynamic performance of an unstented xenograft mitral valve substitute.

OBJECTIVE: Stentless mitral xenografts offer potential clinical benefits because they mimic the normal bileaflet mitral valve. How best to implant them and their hemodynamic performance and durability, however, remain unknown. METHODS: A stentless porcine mitral xenograft valve (Medtronic physiologic mitral valve) was implanted in 7 sheep with papillary muscle sewing tubes attached with transmural left ventricular sutures. Radiopaque markers were inserted on the leaflets, annular cuff, papillary tips, and left ventricle. After 10 +/- 5 days, the animals were studied with biplane videofluoroscopy to determine 3-dimensional marker coordinates at baseline and during dobutamine infusion. Transesophageal echocardiography assessed mitral regurgitation and valvular gradients. Mitral annular area was calculated from the annular markers. Physiologic mitral valve leaflet and annular dynamics were compared with 8 native sheep valves. RESULTS: Average mitral regurgitation grade at baseline was 1.2 +/- 1.0 (range, 0-4), and the mean transvalvular pressure gradients were 3.6 +/- 1.3 and 6.2 +/- 2.2 mm Hg during baseline and dobutamine infusion, respectively. Xenograft mitral annular area contraction throughout the cardiac cycle was reduced (6% +/- 6% vs 13% +/- 4% for physiologic mitral valve and control valve, respectively; P =.03). Physiologic mitral valve leaflet geometry during closure differed from the native valve, with the anterior leaflet being convex to the atrium and with little motion of the posterior leaflet. Three animals survived more than 3 months; good healing of the annular cuff and papillary muscle tubes was demonstrated. CONCLUSION: This stentless xenograft mitral valve substitute had low gradients at baseline and during stress conditions early postoperatively, with mild mitral regurgitation. Preliminary analysis of healing characteristics appeared favorable at 3 months. Additional studies are needed to determine long-term xenograft mitral valve performance and resistance to calcification.