Carotid endarterectomy after systemic thrombolysis in a stroke population.

OBJECTIVE: Vascular specialists are increasingly being requested to perform carotid endarterectomy (CEA) after intravenous thrombolysis (IVT) for stroke patients, raising concerns about hemorrhagic complications. Few case series and registry reports have assessed the question, and even fewer studies have included a control group. The aim of this study was to evaluate the overall outcome of patients undergoing CEA after IVT and to compare them with contemporary patients with CEA after simple stroke (non-IVT group). It also aimed to evaluate the differences in outcomes of stroke patients requiring CEA between nonvascular and vascular centers. METHODS: The data of 169 consecutive patients who have undergone CEA after stroke in a single center was analyzed from January 2011 to December 2016, 27 of them (16%) having undergone previous IVT. A comparative analysis between the non-IVT and the IVT groups was performed. The time between stroke diagnosis and referral to a vascular specialist was also studied. RESULTS: Age, sex, and cardiovascular comorbidities were similar in both groups. Median time between stroke and CEA was 13 days (Q1-Q3, 8-23 days), with 16 of the 27 patients (59%) in the IVT group undergoing CEA less than 14 days after the initial event. There were three intracranial hemorrhages (2.1%) in the non-IVT group versus one (3.7%) in the IVT group (P = NS). The overall 30-day combined stroke and death rate was 7.1% (6.3% in the non-IVT group vs 11.1% in the IVT group; P = .70). The incidence of postoperative cervical hematoma requiring reoperation was similar in both groups (2.1% vs 3.7%; P = NS). The median time between diagnosis of stroke and referral to a vascular specialist was higher for patients in nonvascular centers compared with vascular centers (3.5 days vs 1.0 day; P < .001), which translated to fewer patients referred from nonvascular centers undergoing surgery in the 14-day window period (38% vs 67%; P < .001). CONCLUSIONS: In this retrospective analysis, CEA after IVT showed similar outcomes when compared with the overall CEA after stroke population. Stroke patients diagnosed in nonvascular centers were referred later than those in vascular centers and, although postoperative outcomes were similar, that was correlated with fewer patients undergoing surgery in a timely fashion.

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.

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 cm(2) (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 cm(2), 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 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.

A novel approach for reducing ischemic mitral regurgitation by injection of a polymer to reverse remodel and reposition displaced papillary muscles.

BACKGROUND: Ischemic mitral regurgitation (MR) relates to displacement of the papillary muscles from ischemic ventricular distortion. We tested the hypothesis that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) polymer, a biologically inert biomaterial that has been specially formulated to produce an encapsulated, stable, resilient gel once injected into the myocardium. The purpose is to materially support the infarcted myocardium while at the same time repositioning the papillary muscles that become apically tethered in MR. METHODS AND RESULTS: Nine sheep underwent ligation of circumflex branches to produce acute ischemic MR. PVA polymer was then injected by echo guidance into the myocardium underlying the infarcted papillary muscle. Hemodynamic data, left ventricular ejection fraction, elastance, tau (relaxation constant), left ventricular stiffness coefficient, and 2-dimensional and 3-dimensional echocardiograms were obtained post-MR and post-PVA injection. One animal died after coronary ligation and 2 did not develop MR. In the remaining 6, moderate MR developed. With PVA injection, the MR decreased significantly from moderate to trace-mild (vena contracta: 5+/-0.4 mm versus 2+/-0.7 mm, post-MR versus post-PVA injection; P<0.0001). This was associated with a decrease in infarcted papillary muscle-to-mitral annulus tethering distance (27+/-4 to 24+/-4 mm, post-MR versus post-PVA, P<0.001). Importantly, PVA injection was not associated with significant decreases in left ventricular ejection fraction (43+/-6% versus 37+/-4%, post-MR versus post-PVA, P=nonsignificant), elastance (3.5+/-1.4 versus 2.9+/-1.3; post-MR versus post-PVA injection, P=nonsignificant). Measures of left ventricular diastolic function, tau (100+/-51 ms to 84+/-37 ms, post-MR versus post-PVA; P=nonsignificant), and left ventricular stiffness coefficient (0.18+/-0.12 versus 0.14+/-0.08, post-MR versus post-PVA; P=nonsignificant) did not increase post-PVA. CONCLUSIONS: PVA polymer injection resulted in acute reverse remodeling of the ventricle with papillary muscle repositioning to decrease MR. This was not associated with an adverse effect on left ventricular systolic and diastolic function. This new approach to alter pathological anatomy after infarction may offer an alternative strategy for relieving ischemic MR by correcting the position of the affected papillary muscle, thus relieving apical tethering.

Endobronchial dilation for the management of bronchial stenosis in patients after lung transplantation: effect of stent placement on survival.

PURPOSE: To compare the outcome of patients treated with balloon dilation and stent placement in the management of bronchial strictures after lung transplantation. MATERIALS AND METHODS: Forty-one lung recipients were treated with balloon dilation or stent placement between January 1997 and July 2005. Stent placement was reserved for cases of bronchoplasty technical failure or restenosis. Clinical files and results of pulmonary function tests and bronchoscopic evaluation were reviewed. Dyspnea and cough were defined according to the Breathlessness, Cough, and Sputum Scale. Patient survival and bronchial patency after bronchial intervention were estimated with the Kaplan-Meier method and Cox proportional hazards regression with analysis of stent implantation as a cofactor. RESULTS: Twenty-three of the 41 patients (56%) received a stent because of balloon dilation failure or stenosis recurrence. A total of 243 procedures were performed in 106 strictures (205 bronchoplasties and 38 stent insertions). At the first session, primary patency was higher in patients treated with stents (71%) than in those who underwent bronchoplasty (19%) (P = .037). Mean survival in patients with stents was longer than that in those who underwent bronchoplasty (82 vs 22 months, respectively), and stent insertion was associated with a 66% reduction in the risk of death (P < .02). Primary patency was 40 months for stented strictures versus 10 months for strictures treated with bronchoplasty (P < .02). Dyspnea and cough were improved after intervention (P < .001), and the forced expiratory volume in 1 second (FEV(1)) was ameliorated by 17% (P < .00003) at last follow-up. CONCLUSIONS: Clinical outcome and FEV(1) were improved after bronchoplasty and stent placement. Longer patient survival and bronchial patency were observed after stent insertion.

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.

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 < or = 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. CONCLUSIONS: 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.

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.

Conversion to sinus rhythm does not improve long-term survival after valve surgery: insights from a 20-year follow-up study.

OBJECTIVE: Atrial fibrillation (AF) is frequently associated with valvular heart disease and a common complication of valve surgery. Its contribution to long-term mortality and morbidity remains debated. Our objective was to determine the impact of AF on long-term mortality and embolic complications after valvular surgery and the benefit of conversion to sinus rhythm. This may provide insight to the clinical advantages of surgical anti-AF procedures. METHODS: Data concerning rhythm status, mortality and embolic complications were prospectively collected for 5466 patients with valve surgery. Patients had surgery between 1979 and 2003. Follow-up was complete and all patients had a yearly EKG. RESULTS: Patients with preoperative AF had poorer long-term survival than patients without preoperative AF (20-year survival 23.7 and 33.4%, respectively, P<0.0001). However, preoperative AF was not an independent risk factor of long-term mortality (HR=1.04, P=0.6). In patients with preoperative sinus rhythm, postoperative development of AF had an impact on long-term mortality (HR=1.46, P=0.0012). In patients with preoperative AF, postoperative rhythm did not influence mortality when adjusted for other variables (AF vs. sinus rhythm, HR=1.07, P=0.5709). Mitral valve surgery (HR=1.55, P=0.0270) but not preoperative or postoperative AF had a significant impact on the advent of embolic complications. CONCLUSIONS: The conversion to sinus rhythm did not improve long-term survival or reduce the incidence of embolic complications after valve surgery. Patients with preoperative AF had poorer survival than patients without preoperative AF. AF may be a marker of advanced disease in these patients.

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.

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.

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.

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.

Echocardiographic measures of acute haemodynamic response after cardiac resynchronization therapy predict long-term clinical outcome.

AIMS: Although acute haemodynamic improvement in response to cardiac resynchronization therapy (CRT) is reflective of a favourable cardiac contractile response, there is limited information regarding not only its ability to predict long-term clinical outcome but also cardiac-substrate-specific differences in the prognostic value of this measure. METHODS AND RESULTS: Fifty-three heart failure patients (69 +/- 11 years) with low left ventricle ejection fraction (LVEF) (22 +/- 6%), wide QRS (169 +/- 31 ms), and indications for CRT were included. There were no significant differences in age, New York Heart Association (NYHA) class, medications, QRS width, or LVEF between ischaemic (n = 37) and non-ischaemic (n = 16) groups. Echocardiograms were performed within 24 h of implantation with device OFF and ON. Acute haemodynamic response was measured as LV dP/dt derived from the CW Doppler of mitral regurgitation. Percentage change in dP/dt was used to classify patients: high- (HR: DeltadP/dt > 25%) or poor-responders (PR: DeltadP/dt

Dynamic right ventricular outflow tract obstruction in cardiac surgery.

BACKGROUND: Right ventricular outflow tract obstruction can be a cause of hemodynamic instability but it has not been described in non-congenital cardiac surgery. METHODS: The prevalence of right ventricular outflow tract obstruction was retrospectively studied in 670 consecutive patients undergoing cardiac surgery. Significant right ventricular outflow tract obstruction was diagnosed if the right ventricular systolic to pulmonary artery peak gradient was more than 25 mm Hg. The diagnosis was based on measurement of the right ventricular and pulmonary artery systolic pressure through the paceport and distal opening of the pulmonary artery catheter. To further validate the prevalence and the importance of right ventricular outflow tract obstruction, 130 patients were prospectively studied over a 12-month period. RESULTS: In the retrospective cohort, 6 patients (1%) undergoing various types of cardiac surgical procedures were found to have significant dynamic right ventricular outflow tract obstruction with a mean gradient of 31 +/- 4 mm Hg (26 to 35 mm Hg). In the prospective study significant dynamic right ventricular outflow tract obstruction was identified in 5 patients (4%) (average peak: 37 +/- 15 mm Hg; range: 27 to 60 mm Hg). The typical transesophageal echocardiography finding was end-systolic obliteration of the right ventricular outflow tract. In patients with significant dynamic right ventricular outflow tract obstruction, hemodynamic instability was present in 10/11 patients (91%). CONCLUSIONS: Right ventricular outflow tract obstruction is easily diagnosed using the paceport of the pulmonary artery catheter and should be considered as a potential cause of hemodynamic instability especially when transesophageal echocardiography reveals systolic right ventricular cavity obliteration.