Miguel Chaput

Mitral Leaflet Adaptation to Ventricular Remodeling Occurrence and Adequacy in Patients With Functional Mitral Regurgitation

Background— Functional mitral regurgitation (MR) is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about whether chronic tethering causes the mitral leaflet area to adapt to the geometric needs imposed by tethering, in part because of inability to reconstruct leaflet area in vivo. Our aim was to explore whether adaptive increases in leaflet area occur in patients with functional MR compared with normal subjects and to test the hypothesis that leaflet area influences MR severity. Methods and Results— A new method for 3-dimensional echocardiographic measurement of mitral leaflet area was developed and validated in vivo against 15 sheep heart valves, later excised. This method was then applied in 80 consecutive patients from 3 groups: patients with normal hearts by echocardiography (n=20), patients with functional MR caused by isolated inferior wall-motion abnormality or dilated cardiomyopathy (n=29), and patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (n=31). Leaflet area was increased by 35±20% in patients with LV dysfunction compared with normal subjects. The ratio of leaflet to annular area was 1.95±0.40 and was not different among groups, which indicates a surplus leaflet area that adapts to left-heart changes. In contrast, the ratio of total leaflet area to the area required to close the orifice in midsystole was decreased in patients with functional MR compared with those with normal hearts (1.29±0.15 versus 1.78±0.39, P=0.001) and compared with patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (1.81±0.38, P=0.001). After adjustment for measures of LV remodeling and tethering, a leaflet-to-closure area ratio <1.7 was associated with significant MR (odds ratio 23.2, 95% confidence interval 2.0 to 49.1, P=0.02). Conclusions— Mitral leaflet area increases in response to chronic tethering in patients with inferior wall-motion abnormality and dilated cardiomyopathy, but the development of significant MR is associated with insufficient leaflet area relative to that demanded by tethering geometry. The varying adequacy of leaflet adaptation may explain in part the heterogeneity of this disease among patients. The results suggest the need to understand the mechanisms that underlie leaflet adaptation and whether leaflet area can potentially be modified as part of the therapeutic approach.

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.

Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling: Failure of Hypertrophic Compensation

OBJECTIVES We examined whether mitral regurgitation (MR) augments post-myocardial infarction (MI) remodeling. BACKGROUND MR doubles mortality after MI, but its additive contribution to left ventricular (LV) remodeling is debated and has not been addressed in a controlled fashion. METHODS Apical MIs were created in 12 sheep, and 6 had an LV-to-left atrial shunt implanted, consistently producing regurgitant fractions of approximately 30%. The groups were compared at baseline, 1, and 3 months. RESULTS Left ventricular end-systolic volume progressively increased by 190% with MR versus 90% without MR (p < 0.02). Pre-load-recruitable stroke work declined by 82 +/- 13% versus 25 +/- 16% (p < 0.01) with MR, with decreased remote-zone sarcoplasmic reticulum Ca(2+)-ATPase levels (0.56 +/- 0.03 vs. 0.76 +/- 0.02, p < 0.001), and decreased isolated myocyte contractility. In remote zones, pro-hypertrophic Akt and gp130 were upregulated in both groups at 1 month, but significantly lower and below baseline in the MR group at 3 months. Pro-apoptotic caspase 3 remained high in both groups. Matrix metalloproteinase (MMP)-13 and membrane-type MMP-1 were increased in remote zones of MR versus infarct-only animals at 1 month, then fell below baseline. The MMP tissue inhibitors rose from baseline to 3 months in all animals, rising higher in the MI + MR-group border zone. CONCLUSIONS In this controlled model, moderate MR worsens post-MI remodeling, with reduced contractility. Pro-hypertrophic pathways are initially upregulated but subsequently fall below infarct-only levels and baseline; with sustained caspase 3 elevation, transformation to a failure phenotype occurs. Extracellular matrix turnover increases in MR animals. Therefore, MR can precipitate an earlier onset of dilated heart failure.

Gene Delivery of Sarcoplasmic Reticulum Calcium ATPase Inhibits Ventricular Remodeling in Ischemic Mitral Regurgitation

Background—Mitral regurgitation (MR) doubles mortality after myocardial infarction (MI). We have demonstrated that MR worsens remodeling after MI and that early correction reverses remodeling. Sarcoplasmic reticulum Ca+2-ATPase (SERCA2a) is downregulated in this process. We hypothesized that upregulating SERCA2a might inhibit remodeling in a surgical model of apical MI (no intrinsic MR) with independent MR-type flow. Methods and Results—In 12 sheep, percutaneous gene delivery was performed by using a validated protocol to perfuse both the left anterior descending and circumflex coronary arteries with occlusion of venous drainage. We administered adeno-associated virus 6 (AAV6) carrying SERCA2a under a Cytomegalovirus promoter control in 6 sheep and a reporter gene in 6 controls. After 2 weeks, a standardized apical MI was created, and a shunt was implanted between the left ventricle and left atrium, producing regurgitant fractions of ≈30%. Animals were compared at baseline and 1 and 3 months by 3D echocardiography, Millar hemodynamics, and biopsies. The SERCA2a group had a well-maintained preload-recruitable stroke work at 3 months (decrease by 8±10% vs 42±12% with reporter gene controls; P<0.001). Left ventricular dP/dt followed the same pattern (no change vs 55% decrease; P<0.001). Left ventricular end-systolic volume was lower with SERCA2a (82.6±9.6 vs 99.4±9.7 mL; P=0.03); left ventricular end-diastolic volume, reflecting volume overload, was not significantly different (127.8±6.2 vs 134.3±9.4 mL). SERCA2a sheep showed a 15% rise in antiapoptotic pAkt versus a 30% reduction with the reporter gene (P<0.001). Prohypertrophic activated STAT3 was also 41% higher with SERCA2a than in controls (P<0.001). Proapoptotic activated caspase-3 rose >5-fold during 1 month in both SERCA2a and control animals (P=NS) and decreased by 19% at 3 months, remaining elevated in both groups. Conclusions—In this controlled model, upregulating SERCA2a induced better function and lesser remodeling, with improved contractility, smaller volume, and activation of prohypertrophic/antiapoptotic pathways. Although caspase-3 remained activated in both groups, SERCA2a sheep had increased molecular antiremodeling “tone.” We therefore conclude that upregulating SERCA2a inhibits MR-induced post-MI remodeling in this model and thus may constitute a useful approach to reduce the vicious circle of remodeling in ischemic MR.

Early Repair of Moderate Ischemic Mitral Regurgitation Reverses Left Ventricular Remodeling A Functional and Molecular Study

Background— Mitral regurgitation (MR) doubles postmyocardial infarction (MI) mortality. We have shown that moderate MR augments remodeling in an apical MI model (no intrinsic MR) with independent left ventricle-to-left atrial MR-type flow. We hypothesized that repairing moderate MR 1 month after MI reverses this remodeling. Methods and Results— Anteroapical MIs were created in 18 sheep, and a left ventricle-to-left atrial shunt implanted in 12 (regurgitant fraction, 30%). Six sheep had the shunt closed at 1 month (repair group). Sheep were compared at baseline, and at 1 and 3 months. Sheep in the MI+MR (unrepaired) and repaired groups remodeled during the first month (120% increased left ventricular end-systolic volume [ESV; P<0.01]), but shunt closure reversed remodeling at 3 months, with end-diastolic volume (EDV) and ESV 135% and 128% of baseline versus 220% and 280% without repair (P<0.001). At 3 months, dP/dt and preload-recruitable stroke work were relatively maintained in the repaired and MI-only groups versus nearly 50% decreases without repair. Prohypertrophic gp130 and antiapoptotic pAkt increased followed by exhaustion below baseline without repair, but remained elevated at 3 months with repair or MI only. With repair, matrix metalloproteinase-2 decreased to ≤50% that without repair in remote and border zones at 3 months, and the matrix metalloproteinase inhibitor TIMP-4 increased dramatically. Conclusions— Early repair of moderate MR in the setting of apical MI substantially reverses the otherwise progressive remodeling process, with reduced left ventricular volumes, relatively maintained contractility, persistently activated intracellular signals promoting hypertrophy and opposing apoptosis, and reduced matrix proteolytic activity. These findings are of interest for the current controversy regarding potential benefits of repair of MR after MI.

Chordal Cutting Does Not Adversely Affect Left Ventricle Contractile Function

Background— Severing a limited number of second-order chordae to the anterior leaflet can improve ischemic mitral regurgitation (MR). Some concerns have been raised regarding possible influence on regional and global left ventricle (LV) function. We evaluated changes in cardiac function in 5 normal sheep with cutting of pre-instrumented chords in the beating heart to maintain constant load. Methods and Results— Under cardiopulmonary bypass, wires were placed around the 2 central basal chordae and brought outside the heart, which was restarted. Hemodynamic and imaging data were collected before and after chordal cutting by radiofrequency ablation using those wires. Segmental contractility was assessed invasively using sonomicrometers and noninvasively using Doppler tissue velocity and strain rate (with strain rate viewed as less load-dependent than ejection fraction) at 6 sites: base, mid-ventricle, and apex along the anteroseptal and posterolateral walls. We found no changes from before to after chordal cutting in LV end-diastolic volume (47.2±3.3 after cutting versus 48.4±4.6 mL before cutting, P=0.66), end-systolic volume (21.5±1.2 versus 22.3±2.8 mL, P=0.68), ejection fraction (54.2±1.8 versus 54.2±2.7%, P=0.96), systolic ventricular elastance (7.28±1.68 versus 7.66±2.11 mm Hg/mL, P=0.64), preload-recruitable stroke work (46.6±7.7 versus 50.2±10.7 mm Hg, P=0.76), and LVdP/dt (1480±238 versus 1392±250 mm Hg/s, P=0.45). Doppler tissue velocities and longitudinal strain rates surrounding the papillary muscles were unchanged, as were sonomicrometer longitudinal and mediolateral absolute strains. No wall motion abnormalities were visible around the papillary muscles, and no MR developed. Conclusion— We find no evidence for acutely decreased global or segmental LV contractility with chordal cutting. This absence of adverse effects is consistent with long-term clinical experience with cutting these chords in valve repair.

Persistent Reduction of Ischemic Mitral Regurgitation by Papillary Muscle Repositioning Structural Stabilization of the Papillary Muscle–Ventricular Wall Complex

Background— Recurrent ischemic mitral regurgitation (IMR) is frequent despite initial reduction by annuloplasty because continued LV remodeling increases tethering to the infarcted papillary muscle (PM). We have previously shown that PM repositioning by an external patch device can acutely reduce IMR. In this study, we tested the hypothesis that IMR reduction persists despite possible continued LV remodeling. Methods and Results— In 7 sheep, we used a chronic ischemic posterior infarct model that produces LV dilatation and MR over 10 weeks. An epicardial patch device was adjusted under echo guidance to reduce MR, with follow-up over a further 8 weeks and evaluation by 3D echo and sonomicrometry. In all 7 sheep, moderate IMR resolved with acute patch application and PM repositioning (6.5±1.8 mm to 0.6±1.3 mm proximal jet width, P<0.001) without decrease in LVEF (43±3% to 44±8%). Eight weeks after PM repositioning, MR was not significantly greater (0.6±1.3 mm versus 1.0±1.0 mm, P=NS) despite an increase in LV volumes in 3 animals (2 had increases of 50±15%). On average, LV volumes did not change significantly (ESV: 46±8 mL versus 49±15 mL; P=NS and EDV: 85±16 mL versus 89±30 mL; P=NS). LVEF was unchanged from acute to chronic patch (44±8% versus 43±8%). Contractility as end-systolic elastance did not decrease from the chronic MI to the acute and chronic patch stages, nor were there any significant changes in dP/dt, LV stiffness constant, or time constant of LV relaxation (Tau). Conclusion— PM repositioning is persistently effective in reducing moderate chronic IMR, even when LV volume increases. This may reflect structural stabilization by an external patch device of the papillary muscle-LV wall complex that controls mitral valve tethering.

Validation of Noninvasive Measurements of Cardiac Output in Mice Using Echocardiography

BACKGROUND Although multiple echocardiographic methods exist to calculate cardiac output (CO), they have not been validated in mice using a reference method. METHODS Echocardiographic and flow probe measurements of CO were obtained in mice before and after albumin infusion and inferior vena cava occlusions. Echocardiography was also performed before and after endotoxin injection. Cardiac output was calculated using left ventricular volumes obtained from an M-mode or a two-dimensional view, left ventricular stroke volume calculated using the pulmonary flow, or estimated by the measurement of pulmonary velocity time integral (VTI). RESULTS Close correlations were demonstrated between flow probe-measured CO and all echocardiographic measurements of CO. All echocardiographic-derived CO overestimated the flow probe-measured CO. Two-dimensional image-derived CO was associated with the smallest overestimation of CO. Interobserver variability was lowest for pulmonary VTI-derived CO. CONCLUSION In mice, CO calculated from two-dimensional parasternal long-axis images is most accurate when compared with flow probe measurements; however, pulmonary VTI-derived CO is subject to less variability.

Navigated DENSE strain imaging for post-radiofrequency ablation lesion assessment in the swine left atria.

AIMS Prior work has demonstrated that magnetic resonance imaging (MRI) strain can separate necrotic/stunned myocardium from healthy myocardium in the left ventricle (LV). We surmised that high-resolution MRI strain, using navigator-echo-triggered DENSE, could differentiate radiofrequency ablated tissue around the pulmonary vein (PV) from tissue that had not been damaged by radiofrequency energy, similarly to navigated 3D myocardial delayed enhancement (3D-MDE). METHODS AND RESULTS A respiratory-navigated 2D-DENSE sequence was developed, providing strain encoding in two spatial directions with 1.2 × 1.0 × 4 mm(3) resolution. It was tested in the LV of infarcted sheep. In four swine, incomplete circumferential lesions were created around the right superior pulmonary vein (RSPV) using ablation catheters, recorded with electro-anatomic mapping, and imaged 1 h later using atrial-diastolic DENSE and 3D-MDE at the left atrium/RSPV junction. DENSE detected ablation gaps (regions with >12% strain) in similar positions to 3D-MDE (2D cross-correlation 0.89 ± 0.05). Low-strain (<8%) areas were, on average, 33% larger than equivalent MDE regions, so they include both injured and necrotic regions. Optimal DENSE orientation was perpendicular to the PV trunk, with high shear strain in adjacent viable tissue appearing as a sensitive marker of ablation lesions. CONCLUSIONS Magnetic resonance imaging strain may be a non-contrast alternative to 3D-MDE in intra-procedural monitoring of atrial ablation lesions.