Jacob P. Dal-Bianco

Active Adaptation of the Tethered Mitral Valve Insights Into a Compensatory Mechanism for Functional Mitral Regurgitation

Background— In patients with left ventricular infarction or dilatation, leaflet tethering by displaced papillary muscles frequently induces mitral regurgitation, which doubles mortality. Little is known about the biological potential of the mitral valve (MV) to compensate for ventricular remodeling. We tested the hypothesis that MV leaflet surface area increases over time with mechanical stretch created by papillary muscle displacement through cell activation, not passive stretching. Methods and Results— Under cardiopulmonary bypass, the papillary muscle tips in 6 adult sheep were retracted apically short of producing mitral regurgitation to replicate tethering without confounding myocardial infarction or turbulence. Diastolic leaflet area was quantified by 3-dimensional echocardiography over 61±6 days compared with 6 unstretched sheep MVs. Total diastolic leaflet area increased by 2.4±1.3 cm2 (17±10%) from 14.3±1.9 to 16.7±1.9 cm2 (P=0.006) with stretch with no change in the unstretched valves despite sham open heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18±0.14 versus 0.42±0.14 mm; P<0.0001) at 60 days with an increased spongiosa layer. Endothelial cells (CD31+) coexpressing &agr;-smooth muscle actin were significantly more common by fluorescent cell sorting in tethered versus normal leaflets (41±19% versus 9±5%; P=0.02), indicating endothelial-mesenchymal transdifferentiation. &agr;-Smooth muscle actin-positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial &agr;-smooth muscle actin. Endothelial-mesenchymal transdifferentiation capacity also was demonstrated in cultured MV endothelial cells. Conclusions— Mechanical stresses imposed by papillary muscle tethering increase MV leaflet area and thickness, with cellular changes suggesting reactivated embryonic developmental pathways. Understanding such actively adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic mitral regurgitation.

Mitral Leaflet Adaptation to Ventricular Remodeling Prospective Changes in a Model of Ischemic Mitral Regurgitation

Background— Ischemic mitral regurgitation is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about how chronic tethering affects leaflet area, in part because it cannot be measured repeatedly in situ. Recently, a new method for 3D echocardiographic measurement of mitral leaflet area was developed and validated in vivo against sheep valves, later excised. Clinical studies (n=80) showed that mitral leaflet area increased by >30% in patients with inferior myocardial infarction and dilated cardiomyopathy versus normal; greater adaptation independently predicted less mitral regurgitation. This study explored whether mitral valve area changes over time within the same heart with ischemic mitral regurgitation. Methods and Results— Twelve sheep were studied at baseline and 3 months after inferior myocardial infarction by 3D echocardiography; 6 were untreated and 6 were treated initially with an epicardial patch to limit left ventricular dilation and mitral regurgitation. Untreated sheep developed left ventricular dilation at 3 months, with global dysfunction (mean±SD ejection fraction, 24±10% versus 44±10% with patching, P=0.02) and moderate mitral regurgitation (vena contracta, 5.0±1.0 versus 0.8±1.0 mm, P<0.0002). In untreated sheep, total diastolic leaflet area increased from 13.1±1.3 to 18.1±2.5 cm2 (P=0.0001). In patched sheep, leaflet area at 3 months was not significantly different from baseline sheep values (13.0±1.1 versus baseline, 12.1±1.8 cm2, P=0.31). Conclusions— Mitral valve area, independent of systolic stretch, increases over time as the left ventricular remodels after inferior myocardial infarction. This increase, however, fails to compensate adequately for tethering to prevent mitral regurgitation. Understanding the mechanism of valve adaptation can potentially suggest new biological and surgical therapeutic targets.

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.

Anatomy of the mitral valve apparatus: role of 2D and 3D echocardiography.

The mitral valve apparatus is a complex 3-dimensional (3D) functional unit that is critical to unidirectional heart pump function. This review details the normal anatomy, histology, and function of the main mitral valve apparatus components: mitral annulus, mitral valve leaflets, chordae tendineae, and papillary muscles. Two-dimensional and 3D echocardiography is ideally suited to examine the mitral valve apparatus and has provided important insights into the mechanism of mitral valve disease. An overview of standardized echocardiography image acquisition and interpretation is provided. Understanding normal mitral valve apparatus function is essential to comprehend alterations in mitral valve disease and the rationale for repair strategies.

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.

CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction.

RATIONALE Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation. OBJECTIVE Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro. METHODS AND RESULTS Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45+ endothelial cells (VE-cadherin+/CD45+/α-smooth muscle actin [SMA]+ and VE-cadherin+/CD45+/αSMA- cells) and possible fibrocytes (VE-cadherin-/CD45+/αSMA+) in inferior MI compared with sham-operated and normal sheep. CD45+ cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin+/CD45+/αSMA+ cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-β1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-β1 to 3, not observed in transforming growth factor-β1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells. CONCLUSIONS MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-β1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45+ endothelial cells to MV adaptation and fibrosis post MI warrants investigation.

Mitral Leaflet Changes Following Myocardial InfarctionCLINICAL PERSPECTIVE: 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-&bgr;, 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.

The mitral valve is an actively adapting tissue: new imaging evidence.

With the mitral valve (MV) leaflet bases arising from the mitral annulus (MA) and the leaflet body and tips connected via the chordae and papillary muscles (PM) to the left ventricular (LV) wall, the anterior and posterior MV leaflets are hoisted like sails. The precise systolic spatial and temporal three-dimensional (3D) interplay of all these structures ensures optimal MV leaflet coaptation within the LV cavity just at the level of the MA, while preventing leaflet displacement into the left atrium (LA; prolapse) or the LV outflow tract (systolic anterior motion, SAM). Any change in form or function that leads to an imbalance of this interplay can result in mechanical leaflet stretch, and if leaflet redundancy is exhausted, to a relative leaflet tissue to MA area deficit and therefore mitral regurgitation (MR).1 Gradually evolving changes that do not unsettle this balance, such as fetal to adulthood growth, seem to allow the MV leaflets to adapt, grow and match the needs of the enlarging LV and MA (×20 area increase).2 The …

Evolution of secondary mitral regurgitation

Aims Secondary mitral regurgitation (MR) drives adverse remodelling towards late heart failure stages. Little is known about the evolution of MR under guideline-directed therapy (GDT) and its relation to cardiac remodelling and outcome. We therefore aimed to assess incidence, impact, and predictors of progressive secondary MR in patients under GDT. Methods and results We prospectively enrolled 249 patients with chronic heart failure and reduced ejection fraction receiving GDT in this long-term observational study. Of patients with non-severe MR at baseline 81% remained stable whereas 19% had progressive MR. Those patients were more symptomatic (P < 0.001), had higher neurohumoral activation (encompassing various neurohumoral pathways in heart failure, all P < 0.05), larger left atrial size (P = 0.004) and more tricuspid regurgitation (TR, P = 0.02). During a median follow-up of 61 months (IQR 50-72), 61 patients died. Progression of MR conveyed an increased risk of mortality-univariately (HR 2.33; 95% CI 1.34-4.08; P = 0.003), that persisted after multivariate adjustment using a bootstrap-selected confounder model (adjusted HR 2.48; 95% CI 1.40-4.39; P = 0.002). In contrast, regression of MR was not associated with a beneficiary effect on outcome (crude HR 0.84; 95% CI 0.30-2.30; P = 0.73). Conclusions Every fifth patient with chronic heart failure suffers from MR progression. This entity is associated with a more than two-fold increased risk of death even after careful multivariable adjustment. Symptomatic status, left atrial size, TR, and neurohumoral pathways help to identify patients at risk for progressive secondary MR in an early disease process and open the possibility for closer follow-up and timely intervention.

Minimally Invasive Mitral Valve Surgery via Mini-Thoracotomy: Current Update

Opinion statementIn recent years, minimally invasive mitral valve surgery (MIMVS) has established itself as an alternative and increasingly used option for patients with mitral valve (MV) pathology. MIMVS is associated with a very low perioperative morbidity and mortality rate in appropriately selected patients, comparable to a full sternotomy approach. Besides superior cosmetic results, patients after MIMVS enjoy shorter recovery times and earlier returns to full activity. A number of approaches are branded as minimally invasive, but the most widely used one entails peripheral cardiopulmonary bypass and a small right anterolateral mini-thoracotomy. The operative technique and outcomes of this approach are summarized in the current update.