Abstract 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-β, 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.
AbstractObjectiveVascular 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. MethodsThe 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. ResultsAge, 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). ConclusionsIn 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.
Although multiple echocardiographic methods exist to calculate cardiac output (CO), they have not been validated in mice using a reference method.
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).
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.
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.
Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling: Failure of Hypertrophic Compensation Ronen Beeri, Chaim Yosefy, J. Luis Guerrero, Francesca Nesta, Suzan Abedat, Miguel Chaput, ...Federica del Monte, Mark D. Handschumacher, Robert Stroud, Suzanne Sullivan, Thea Pugatsch, Dan Gilon, Gus J. Vlahakes, Francis G. Spinale, Roger J. Hajjar, Robert A. Levine Mitral regurgitation (MR) doubles mortality after myocardial infarction (MI), but its additive contribution to left ventricular remodeling is debated and has not been addressed in a controlled fashion. In a sheep model with apical MI and a standard moderate MR, we observed excess remodeling as compared with MI without MR, as manifested by increased gross remodeling morphology by 3-dimensional echocardiography, reduced intrinsic contractility at the global and cellular levels, exhaustion of pro-hypertrophic signaling in the cardiomyocytes, and increased extracellular matrix turnover. Hence, MR worsens post-MI remodeling.
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.
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.
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.
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.
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.
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.
To compare the outcome of patients treated with balloon dilation and stent placement in the management of bronchial strictures after lung transplantation.
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.
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.
Clinical outcome and FEV(1) were improved after bronchoplasty and stent placement. Longer patient survival and bronchial patency were observed after stent insertion.
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