Effects of Cyproheptadine on Mitral Valve Remodeling and Regurgitation After Myocardial Infarction.

BACKGROUND: Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR). OBJECTIVES: This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology. METHODS: Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals. RESULTS: Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals. CONCLUSIONS: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR.

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

BACKGROUND: Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves. OBJECTIVES: This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves. METHODS: Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves. RESULTS: Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm2 vs. 15.1 ± 1.6 cm2, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group. CONCLUSIONS: In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.

Mechanical effects of MitraClip on leaflet stress and myocardial strain in functional mitral regurgitation - A finite element modeling study.

PURPOSE: MitraClip is the sole percutaneous device approved for functional mitral regurgitation (MR; FMR) but MR recurs in over one third of patients. As device-induced mechanical effects are a potential cause for MR recurrence, we tested the hypothesis that MitraClip increases leaflet stress and procedure-related strain in sub-valvular left ventricular (LV) myocardium in FMR associated with coronary disease (FMR-CAD). METHODS: Simulations were performed using finite element models of the LV + mitral valve based on MRI of 5 sheep with FMR-CAD. Models were modified to have a 20% increase in LV volume (↑LV_VOLUME) and MitraClip was simulated with contracting beam elements (virtual sutures) placed between nodes in the center edge of the anterior (AL) and posterior (PL) mitral leaflets. Effects of MitraClip on leaflet stress in the peri-MitraClip region of AL and PL, septo-lateral annular diameter (SLAD), and procedure-related radial strain (Err) in the sub-valvular myocardium were calculated. RESULTS: MitraClip increased peri-MitraClip leaflet stress at end-diastole (ED) by 22.3±7.1 kPa (p<0.0001) in AL and 14.8±1.2 kPa (p<0.0001) in PL. MitraClip decreased SLAD by 6.1±2.2 mm (p<0.0001) and increased Err in the sub-valvular lateral LV myocardium at ED by 0.09±0.04 (p<0.0001)). Furthermore, MitraClip in ↑LV_VOLUME was associated with persistent effects at ED but also at end-systole where peri-MitraClip leaflet stress was increased in AL by 31.9±14.4 kPa (p = 0.0268) and in PL by 22.5±23.7 kPa (p = 0.0101). CONCLUSIONS: MitraClip for FMR-CAD increases mitral leaflet stress and radial strain in LV sub-valvular myocardium. Mechanical effects of MitraClip are augmented by LV enlargement.

Mitral Valve Adaptation to Isolated Annular Dilation: Insights Into the Mechanism of Atrial Functional Mitral Regurgitation.

OBJECTIVES: This study hypothesized that compensatory mitral leaflet area (MLA) adaptation occurs in patients with persistent atrial fibrillation (AF) without left ventricular (LV) dysfunction but has limitations that augment mitral regurgitation (MR). The study also explored whether asymmetrical annular dilation is matched by relative leaflet enlargement. BACKGROUND: Functional MR occurs in patients with AF and isolated annular dilation, but the relationship of MLA adaptation with annular area (AA) is unknown. METHODS: Three-dimensional echocardiographic images were acquired from 86 patients with quantified MR: 53 with nonvalvular persistent AF (23 MR+ with moderate or greater MR, 30 MR-) without LV dysfunction or dilation and 33 normal controls. Comprehensive 3-dimensional analysis included total diastolic MLA, adaptation ratios of MLA to annular area and MLA to leaflet closure area, and annular and tenting geometry. RESULTS: Total MLA was 22% larger in patients with AF than in controls, thus paralleling the increased AA. However, as AA increased, adaptive indices (MLA/AA ratio and ratio of MLA to closure area) plateaued, becoming lowest in MR+ patients (ratio of MLA to closure area = 1.63 ± 0.17 controls, 1.60 ± 0.11 MR-, 1.32 ± 0.10 MR+; p < 0.001). MR increased as the ratio of MLA to closure area decreased (R2 = 0.68; p < 0.001). The posterior-to-anterior MLA ratio remained constant, whereas the posterior-to-anterior mitral annulus perimeter increased (1.21 ± 0.16 controls, 1.32 ± 0.20 MR-, 1.46 ± 0.19 MR+; p < 0.001). Multivariate MR determinants were annular area, total MLA to closure area, and posterior-to-anterior perimeter ratios. CONCLUSIONS: MLA adaptively increases in AF with isolated annular dilation and normal LV function. This compensatory enlargement becomes insufficient with greater annular dilation, and the leaflets fail to match asymmetrical annular remodeling, thereby increasing MR. These findings can potentially help optimize therapeutic options and motivate basic studies of adaptive growth processes.

Mitral Leaflet Changes Following Myocardial Infarction: Clinical Evidence for Maladaptive Valvular Remodeling.

BACKGROUND: Ischemic mitral regurgitation (MR) is classically ascribed to functional restriction of normal leaflets, but recent studies have suggested post-myocardial infarction (MI) mitral valve (MV) leaflet fibrosis and thickening, challenging valve normality. Progression of leaflet thickness post-MI has not been studied. We hypothesized that excessive MV remodeling post-MI contributes to MR. Our objectives are to characterize MV changes after MI and relate them to MR. METHODS AND RESULTS: Three groups of 40 patients with serial echocardiograms over a mean of 23.4 months were identified from an echocardiography database: patients first studied early (6±12 days) and late (12±7 years) after an inferior MI and normal controls. MV thickness was correlated with MR. We studied the mechanisms for MV changes in a sheep model (6 apical MI versus 6 controls) followed for 8 weeks, with MV cellular and histopathologic analyses. Early post-MI, leaflet thickness was found to be similar to controls (2.6±0.5 vs 2.5±0.4 mm; P=0.23) but significantly increased over time (2.5±0.4 to 2.9±0.4 mm; P<0.01). In this group, patients tolerating maximal doses of renin-angiotensin blocking agents had less thickening (25% of patients; P<0.01). The late-MI group had increased thickness (3.2±0.5 vs 2.5±0.4 mm; P<0.01) without progression. At follow-up, 48% of post-MI patients had more than mild MR. Increased thickness was independently associated with MR. Experimentally, 8 weeks post-MI, MVs were 2-fold thicker than controls, with increased collagen, profibrotic transforming growth factor-ß, and endothelial-to-mesenchymal transformation, confirmed by flow cytometry. CONCLUSIONS: MV thickness increases post-MI and correlates with MR, suggesting an organic component to ischemic MR. MV fibrotic remodeling can indicate directions for future therapy.

Acute Leukemia is Associated with Cardiac Alterations before Chemotherapy.

BACKGROUND: Patients with acute leukemia (AL) have a higher rate of congestive heart failure than patients with other cancers. AL may predispose to cardiac dysfunction before chemotherapy because of high cytokine release or direct leukemic myocardial infiltration. The aims of this study were to evaluate whether AL is associated with abnormalities of myocardial structure and function before chemotherapy and to identify possible risk factors associated with these myocardial changes. METHODS: Using an echocardiographic database, 76 patients with AL and 76 patients without cancer matched for age, gender, hypertension, and the presence of diabetes were retrospectively selected. Subsequently, to assess the effect of a nonhematologic malignancy, 28 women in each group were matched with women with breast cancer. Left ventricular (LV) mass, volumes, ejection fraction, and global longitudinal strain (GLS) were measured before chemotherapy. RESULTS: The patients were predominantly male (63%), with a median age of 51 years, and had low prevalence of cardiovascular risk factors. Despite similar LV ejection fractions, patients with AL had higher LV mass and volumes and lower GLS (-19.3 ± 2.7% vs -20.9 ± 1.9%, P < .001) than patients without cancer. Similarly, GLS was lower in women with AL compared with women with breast cancer or without cancer. Among patients with AL, high body mass index, low LV ejection fraction, and a small number of circulating lymphocytes were all independently associated with low GLS. CONCLUSIONS: Patients with AL had higher LV volumes and lower GLS than patients without cancer and lower GLS than patients with breast cancer, suggesting that AL by itself may be associated with these cardiac alterations.

Effect of Losartan on Mitral Valve Changes After Myocardial Infarction.

BACKGROUND: After myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth, but counterproductive leaflet thickening and fibrosis augment mitral regurgitation (MR), doubling heart failure and mortality. MV fibrosis post-MI is associated with excessive endothelial-to-mesenchymal transition (EMT), driven by transforming growth factor (TGF)-ß overexpression. In vitro, losartan-mediated TGF-ß inhibition reduces EMT of MV endothelial cells. OBJECTIVES: This study tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF-ß inhibition. METHODS: The study assessed 17 sheep, including 6 sham-operated control animals and 11 with apical MI and papillary muscle retraction short of producing MR; 6 of the 11 were treated with daily losartan, and 5 were untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by using three-dimensional echocardiography at baseline and at 60 ± 6 days, and excised leaflets were analyzed by histopathology and flow cytometry. RESULTS: Post-MI LV dilation and tethering were comparable in the losartan-treated and untreated LV constraint sheep. Telemetered sensors (n = 6) showed no significant losartan-induced changes in arterial pressure. Losartan strongly reduced leaflet thickness (0.9 ± 0.2 mm vs. 1.6 ± 0.2 mm; p < 0.05; 0.4 ± 0.1 mm sham animals), TGF-ß, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 ± 12.0% vs. 51.6 ± 11.7% α-smooth muscle actin-positive endothelial cells, p < 0.05; 7.2 ± 3.5% sham animals), cellular proliferation, collagen deposition, endothelial cell activation (vascular cell adhesion molecule-1 expression), neovascularization, and cells positive for cluster of differentiation (CD) 45, a hematopoietic marker associated with post-MI valve fibrosis. Leaflet area increased comparably (17%) in constrained and losartan-treated sheep. CONCLUSIONS: Profibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth. Understanding the cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR.

Contraction Timing Patterns in Patients Treated for Breast Cancer Before and After Anthracyclines Therapy.

BACKGROUND: During the development of heart failure (HF), the changes of contraction timing pattern and temporal heterogeneity of segmental contraction happen early and may precede both symptomatic HF and the decrease in left ventricular ejection fraction (LVEF). In patients treated with anthracyclines, both symptomatic HF and the decrease of LVEF are detected once significant myocardial injury has occurred. The aim of the current study was to investigate whether changes in the timing of contraction can be detected early after anthracyclines therapy. METHODS: Forty-one women (50 ± 11 years old) with newly diagnosed breast cancer were prospectively enrolled in two centers and underwent an echocardiogram before and after anthracyclines. Peak longitudinal myocardial systolic strain was measured on the apical four- and two-chamber views. The time to peak systolic longitudinal strain (TP), ejection time (ET), isovolumic contraction time (IVCT), systolic time, and diastolic time were measured using strain curves and Doppler tracings and compared before and after anthracyclines. The heterogeneity of contraction (dyssynchrony) was measured by the SD of the TP of all segments. RESULTS: Anthracyclines treatment was associated with an increase in heart rate (HR) and a decrease in TP. TP was correlated with HR. TP/ET was independent of HR and inversely correlated to peak strain both at baseline and after anthracyclines. TP/ET increased after anthracyclines (1.26 ± 0.19 to 1.31 ± 0.22; P < .001), and this increase was correlated with the decrease in strain. The increase in TP/ET was due to an increase in IVCT/ET. A similar degree of dyssynchrony was found at baseline and after anthracyclines. CONCLUSIONS: Anthracyclines treatment induces an increase in the duration of contraction, mainly by increasing the IVCT. This increase is correlated to the decrease in strain and may therefore have additional prognostic value.

In vivo assessment of aortic root geometry in normal controls using 3D analysis of computed tomography.

AIMS: Understanding normal asymmetry in the aortic root could aid in the development of new surgical repair techniques or devices with improved haemodynamic performance. The purpose of this study was to assess geometric asymmetry and age-related changes in the normal aortic root using 3D computed tomography. METHODS AND RESULTS: The institutional review board approved this retrospective study of 130 normal subjects (mean age, 51.4 years; 58 men). Specialized 3D software measured individual cusp sinus volumes (CSVs), cusp surface areas (CSAs), and intercommissural distances (ICDs). Age-related aortic root changes were evaluated with simple correlation, ANOVA test among age groups, and multivariable linear regression analyses. The CSV and CSA of left coronary cusp (LCC) were significantly smaller than those of right coronary cusp (RCC) and non-coronary cusp (NCC) (both, P < 0.001) in all age groups. The mean ratios of RCC or NCC-to-LCC were 1.38 and 1.36 for CSV, 1.19 and 1.20 for CSA, and 1.21 and 1.06 for ICD, respectively. The CSV and ICD increased in older age with weak-to-moderate correlation coefficients in both men and women. By multivariable linear regression, CSVs and ICDs of all cusps showed a positive correlation with age (P < 0.05), and the female gender was associated with a smaller size of the CSV and CSA. CONCLUSIONS: The LCC was significantly smaller than the other two cusps, and the aortic root size increased with age.

Myocardial Infarction Alters Adaptation of the Tethered Mitral Valve.

BACKGROUND: In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition. OBJECTIVES: The aim of this study was to explore the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies mitral valve adaptation. METHODS: Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the papillary muscle tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered alone). Papillary muscle retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered plus MI), and left ventricular remodeling was limited by external constraint in 5 additional sheep (left ventricular constraint). Six sham-operated sheep were control subjects. Diastolic mitral valve surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets. RESULTS: Tethered plus MI leaflets were markedly thicker than tethered-alone valves and sham control subjects. Leaflet area also increased significantly. Endothelial-to-mesenchymal transition, detected as α-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-ß, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering plus MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered plus MI findings were comparable with external ventricular constraint. CONCLUSIONS: MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR.

Mitral valve disease--morphology and mechanisms.

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but--even in adult life--remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

Leaflet area as a determinant of tricuspid regurgitation severity in patients with pulmonary hypertension.

BACKGROUND: Tricuspid regurgitation (TR) is a risk factor for mortality in pulmonary hypertension (PH). TR severity varies among patients with comparable degrees of PH and right ventricular remodeling. The contribution of leaflet adaptation to the pathophysiology of TR has yet to be examined. We hypothesized that tricuspid leaflet area (TLA) is increased in PH, and that the adequacy of this increase relative to right ventricular remodeling determines TR severity. METHODS AND RESULTS: A prospective cohort of 255 patients with PH from pre and postcapillary pathogeneses was assembled from 2 centers. Patients underwent a 3-dimensional echocardiogram focused on the tricuspid apparatus. TLA was measured with the Omni 4D software package. Compared with normal controls, patients with PH had a 2-fold increase in right ventricular volumes, 62% increase in annular area, and 49% increase in TLA. Those with severe TR demonstrated inadequate increase in TLA relative to the closure area, such that the ratio of TLA:closure area <1.78 was highly predictive of severe TR (odds ratio, 68.7; 95% confidence interval, 16.2-292.7). The median vena contracta width was 8.5 mm in the group with small TLA and large closure area as opposed to 4.8 mm in the group with large TLA and large closure area. CONCLUSIONS: TLA plays a significant role in determining which patients with PH develop severe functional TR. The ratio of TLA:closure area, reflecting the balance between leaflet adaptation versus annular dilation and tethering forces, is an indicator of TR severity that may identify which patients stand to benefit from leaflet augmentation during tricuspid valve repair.

Efficacy of polymer injection for ischemic mitral regurgitation: persistent reduction of mitral regurgitation and attenuation of left ventricular remodeling.

OBJECTIVES: The aim of this study was to examine the chronic effects of polyvinyl-alcohol (PVA) injection on mitral regurgitation (MR) reduction, mitral valve geometry, and left ventricular (LV) remodeling in a chronic ischemic MR sheep model. BACKGROUND: Previous studies have demonstrated acute efficacy of PVA hydrogel polymer injection into infarcted myocardium underlying the papillary muscle to relieve MR by papillary muscle repositioning. However, the chronic efficacy of PVA injection in the chronic infarction setting remains unclear. METHODS: Sixteen sheep developed chronic MR 8 weeks after induced inferoposterior myocardial infarction. Ten consecutive sheep underwent PVA injection (PVA group) and 6 sheep served as control subjects with saline injection. Epicardial 2-/3-dimensional echocardiography was performed at the baseline, chronic MR (pre-injection), and sacrifice (8 weeks after injection) stages. RESULTS: Both groups were comparable at the baseline and chronic MR stages. At sacrifice, MR decreased from moderate to trace or mild (vena contracta: 0.17 ± 0.08 cm vs. 0.56 ± 0.10 cm, p < 0.001) in the PVA group but progressed to moderate to severe in the control group. End-systolic and -diastolic volumes remained stable in the PVA group but increased significantly in the control group (both p < 0.05). At sacrifice, compared with the control group, the PVA group had significantly less left ventricular remodeling (end-systolic volume: 41.1 ± 10.4 ml vs. 55.9 ± 12.4 ml, p < 0.05), lower MR severity (vena contracta: 0.17 ± 0.08 cm vs. 0.60 ± 0.14 cm, p < 0.01), and favorable changes in mitral valve geometry. CONCLUSIONS: Polymer injection in a chronic ischemic MR model results in persistent reduction of MR and attenuation of continued left ventricular remodeling over 8 weeks of follow-up.

Basic mechanisms of mitral regurgitation.

Any structural or functional impairment of the mitral valve (MV) apparatus that exhausts MV tissue redundancy available for leaflet coaptation will result in mitral regurgitation (MR). The mechanism responsible for MV malcoaptation and MR can be dysfunction or structural change of the left ventricle, the papillary muscles, the chordae tendineae, the mitral annulus, and the MV leaflets. The rationale for MV treatment depends on the MR mechanism and therefore it is essential to identify and understand normal and abnormal MV and MV apparatus function.

Aortic valve adaptation to aortic root dilatation: insights into the mechanism of functional aortic regurgitation from 3-dimensional cardiac computed tomography.

BACKGROUND: The 3-dimensional relationship between aortic root and cusp is essential to understand the mechanism of aortic regurgitation (AR) because of aortic root dilatation (ARD). We sought to test the hypothesis that the stretched cusps in ARD enlarge to compensate for ARD. METHODS AND RESULTS: Computed tomography imaged 92 patients (57 with ARD, 29 with moderate to severe AR, 28 without significant AR) and 35 normal controls. Specialized 3-dimensional software measured individual cusp surface areas relative to maximal mid-sinus cross-sectional area and minimal 3-dimensional annular area, coaptation area fraction, and asymmetry of sinus volumes and intercommissural distances. Total open cusp surface area increased (P<0.001) from 7.6±1.4 cm(2)/m(2) in normals to 12.9±2.2 cm(2)/m(2) in AR-negative and 15.2±3.3 cm(2)/m(2) in AR-positive patients. However, the ratio of closed cusp surface area to maximal mid-sinus area, reflecting cusp adaptation, decreased from normals to AR-negative to AR-positive patients (1.38±0.20, 1.15±0.15, 0.88±0.15; P<0.001), creating the lowest coaptation area fraction. Cusp distensibility (closed diastolic versus open area) decreased from 20% in controls and AR-negative patients to 5% in AR-positive patients (P<0.001). Multivariate determinants of AR and coaptation area fraction reflected both sinus size and cusp-to-annular adaptation. ARD was also progressively asymmetrical with root size, and individual cusp surface areas failed to match this asymmetry. CONCLUSIONS: Aortic cusp enlargement occurs in ARD, but cusp adaptation and distensibility become limited in prominent, asymmetrical ARD, leading to AR. Optimal AR repair tailored to individual patient anatomy can benefit from appreciating valve adaptation and 3-dimensional relationships; understanding cusp adaptation mechanisms may ultimately provide therapeutic opportunities to improve such compensation.

Role of LA shape in predicting embolic cerebrovascular events in mitral stenosis: mechanistic insights from 3D echocardiography.

OBJECTIVES: This study was designed to assess the role of left atrial (LA) shape in predicting embolic cerebrovascular events (ECE) in patients with mitral stenosis (MS). BACKGROUND: Patients with rheumatic MS are at increased risk for ECE. LA remodeling in response to MS involves not only chamber dilation but also changes in the shape. We hypothesized that a more spherical LA shape may be associated with increased embolic events due to predisposition to thrombus formation or to atrial arrhythmias compared with an elliptical-shaped LA of comparable volume. METHODS: A total of 212 patients with MS and 20 control subjects were enrolled. LA volume, LA emptying fraction, and cross-sectional area were measured by 3-dimensional (3D) transthoracic echocardiography. LA shape was expressed as the ratio of measured LA end-systolic volume to hypothetical sphere volume ([4/3π r(3)] where r was obtained from 3D cross-sectional area). The lower the LA shape index, the more spherical the shape. RESULTS: A total of 41 patients presented with ECE at the time of enrollment or during follow-up. On multivariate analysis, LA 3D emptying fraction (adjusted odds ratio [OR]: 0.96; 95% confidence interval [CI]: 0.92 to 0.99; p = 0.028) and LA shape index (OR: 0.73; 95% CI: 0.61 to 0.87; p < 0.001) emerged as important factors associated with ECE, after adjustment for age and anticoagulation therapy. In patients in sinus rhythm, LA shape index remained associated with ECE (OR: 0.79; 95% CI: 0.67 to 0.94; p = 0.007), independent of age and LA function. An in vitro phantom atrial model demonstrated more stagnant flow profiles in spherical compared with ellipsoidal chamber. CONCLUSIONS: In rheumatic MS patients, differential LA remodeling affects ECE risk. A more spherical LA shape was independently associated with an increased risk for ECE, adding incremental value in predicting events beyond that provided by age and LA function.

The echo score revisited: Impact of incorporating commissural morphology and leaflet displacement to the prediction of outcome for patients undergoing percutaneous mitral valvuloplasty.

BACKGROUND: Current echocardiographic scoring systems for percutaneous mitral valvuloplasty (PMV) have limitations. This study examined new, more quantitative methods for assessing valvular involvement and the combination of parameters that best predicts immediate and long-term outcome after PMV. METHODS AND RESULTS: Two cohorts (derivation n=204 and validation n=121) of patients with symptomatic mitral stenosis undergoing PMV were studied. Mitral valve morphology was assessed by using both the conventional Wilkins qualitative parameters and novel quantitative parameters, including the ratio between the commissural areas and the maximal excursion of the leaflets from the annulus in diastole. Independent predictors of outcome were assigned a points value proportional to their regression coefficients: mitral valve area ≤1 cm(2) (2), maximum leaflets displacement ≤12 mm (3), commissural area ratio ≥1.25 (3), and subvalvular involvement (3). Three risk groups were defined: low (score of 0-3), intermediate (score of 5), and high (score of 6-11) with observed suboptimal PMV results of 16.9%, 56.3%, and 73.8%, respectively. The use of the same scoring system in the validation cohort yielded suboptimal PMV results of 11.8%, 72.7%, and 87.5% in the low-, intermediate-, and high-risk groups, respectively. The model improved risk classification in comparison with the Wilkins score (net reclassification improvement 45.2%; P<0.0001). Long-term outcome was predicted by age and postprocedural variables, including mitral regurgitation, mean gradient, and pulmonary pressure. CONCLUSIONS: A scoring system incorporating new quantitative echocardiographic parameters more accurately predicts outcome following PMV than existing models. Long-term post-PMV event-free survival was predicted by age, degree of mitral regurgitation, and postprocedural hemodynamic data.

Late repair of ischemic mitral regurgitation does not prevent left ventricular remodeling: importance of timing for beneficial repair.

BACKGROUND: Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction associated with left ventricular (LV) dilatation and dysfunction, which doubles mortality. At the molecular level, moderate ischemic MR is characterized by a biphasic response, with initial compensatory rise in prohypertrophic and antiapoptotic signals, followed by their exhaustion. We have shown that early MR repair 30 days after myocardial infarction is associated with LV reverse remodeling. It is not known whether MR repair performed after the exhaustion of compensatory mechanisms is also beneficial. We hypothesized that late repair will not result in LV reverse remodeling. METHODS AND RESULTS: Twelve sheep underwent distal left anterior descending coronary artery ligation to create apical myocardial infarction and implantation of an LV-to-left atrium shunt to create standardized moderate volume overload. At 90 days, animals were randomized to shunt closure (late repair) versus sham (no repair). LV remodeling was assessed by 3-dimensional echocardiography, dP/dt, preload-recruitable stroke work, and myocardial biopsies. At 90 days, animals had moderate volume overload, LV dilatation, and reduced ejection fraction (all P<0.01 versus baseline, P=NS between groups). Shunt closure at 90 days corrected the volume overload (regurgitant fraction 6 ± 5% versus 27 ± 16% for late repair versus sham, P<0.01) but was not associated with changes in LV volumes (end-diastolic volume 106 ± 15 versus 110 ± 22 mL; end-systolic volume 35 ± 6 versus 36 ± 6 mL) or increases in preload-recruitable stroke work (41 ± 7 versus 39 ± 13 mL mm Hg) or dP/dt (803 ± 210 versus 732 ± 194 mm Hg/s) at 135 days (all P=NS). Activated Akt, central in the hypertrophic process, and signal transducer and activator of transcription 3 (STAT3), a critical node in the hypertrophic stimulus by cytokines, were equally depressed in both groups. CONCLUSIONS: Late correction of moderate volume overload after myocardial infarction did not improve LV volume or contractility. Upregulation of prohypertrophic intracellular pathways was not observed. This contrasts with previously reported study in which early repair (30 days) reversed LV remodeling. This suggests a window of opportunity to repair ischemic MR after which no beneficial effect on LV is observed, despite successful repair.

Mechanisms of functional mitral regurgitation in ischemic cardiomyopathy determined by transesophageal echocardiography (from the Surgical Treatment for Ischemic Heart Failure Trial).

The mechanisms underlying functional mitral regurgitation (MR) and the relation between mechanism and severity of MR have not been evaluated in a large, multicenter, randomized controlled trial. Transesophageal echocardiography (TEE) was performed in 215 patients at 17 centers in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Both 2-dimensional (n = 215) and 3-dimensional (n = 81) TEEs were used to assess multiple quantitative measurements of the mechanism and severity of MR. By 2-dimensional TEE, leaflet tenting area, anterior and posterior leaflet angles, mitral annulus diameter, left ventricular (LV) end-systolic volume index, LV ejection fraction (LVEF), and sphericity index (p <0.05 for all) were significantly different across MR grades. By 3-dimensional TEE, mitral annulus area, leaflet tenting area, LV end-systolic volume index, LVEF, and sphericity index (p <0.05 for all) were significantly different across MR grades. A multivariate analysis showed a trend for annulus area (p = 0.069) and LV end-systolic volume index (p = 0.071) to predict effective regurgitant orifice area and for annulus area (p = 0.018) and LV end-systolic volume index (p = 0.073) to predict vena contracta area. In the STICH trial, multiple quantitative parameters of the mechanism of functional MR are related to MR severity. The mechanism of functional MR in ischemic cardiomyopathy is heterogeneous, but no single variable stands out as a strong predictor of quantitative severity of MR.