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* 10,870,978 کتاب کتاب * 84,837,646 مضامین مضامین * Z-Library Home * ہوم پیج نیویگیشن ٹوگل کریں * سائن ان کریں * لاگ ان * رجستریشن * عطیہ کریں * * × * * رسائل * * Top Z-Librarians * Blog مرکزی صفحہ Cardiovascular Pathology Histopathologic correlates of myocardial improvement in patients supported by a left ventricular... Cardiovascular Pathology 2011 Vol. 20; Iss. 3 Histopathologic correlates of myocardial improvement in patients supported by a ... Ana Maria Segura; O.H. Frazier; Zumrut Demirozu; L. Maximilian B... HISTOPATHOLOGIC CORRELATES OF MYOCARDIAL IMPROVEMENT IN PATIENTS SUPPORTED BY A LEFT VENTRICULAR ASSIST DEVICE Ana Maria Segura, O.H. Frazier, Zumrut Demirozu, L. Maximilian Buja آپ کو یہ کتاب کتنی پسند ہے؟ فائل کی کوالٹی کیا ہے؟ کوالٹی کا جائزہ لینے کے لیے کتاب ڈاؤن لوڈ کریں فائل کی کوالٹی کیا ہے؟ جلد: 20 سال: 2011 زبان: english صفحات: 146 DOI: 10.1016/j.carpath.2010.01.011 فائل: PDF, 1.98 MB آپ کے ٹیگز: ڈاؤن لوڈ کریں (pdf, 1.98 MB) براؤزر میں کھولیں * براؤزر میں کھولیں پیش نظارہ Send-to-Kindle Send to بعد دیکہنے کے لئے کو بچانے کے مسئلے کے بارے میں بتائیے File opens جی ہاں نہیں This is a book جی ہاں نہیں Content is appropriate جی ہاں نہیں Description matches جی ہاں نہیں Are you sure the file is of bad quality? Report about it Check Yes if Check Yes if Check Yes if Check Yes if you were able to open the file the file contains a book (comics are also acceptable) the content of the book is acceptable Title, Author and Language of the file match the book description. Ignore other fields as they are secondary! Check No if Check No if Check No if Check No if * the file is damaged * the file is DRM protected * the file is not a book (e.g. executable, xls, html, xml) * the file is an article * the file is a book excerpt * the file is a magazine * the file is a test blank * the file is a spam you believe the content of the book is unacceptable and should be blocked Title, Author or Language of the file do not match the book description. Ignore other fields. This book has a different problem? Report it to us Are you sure the file is of bad quality? Report about it Send a report Change your answer Thanks for your participation! Together we will make our library even better فائل آپ کے ای میل ایڈریس پر بھیجی جائگی۔ اسے موصول ہونے میں 5 منٹ تک کا وقت لگ سکتا ہے۔. فائل آپ کے Kindle اکاؤنٹ پر بھیجی جائگی۔ اسے موصول ہونے میں 5 منٹ تک کا وقت لگ سکتا ہے۔. نوٹ کریں : آپ کو ہر کتاب کی تصدیق کرنی ہوگی جسے آپ اپنے Kindle میں بھیجنا چاہیں۔ Amazon Kindle سے تصدیقی ای میل کے لیے اپنا میل باکس چیک کریں۔ Conversion to is in progress Conversion to is failed 0 comments معائنہ پوسٹ کریں To post a review, please sign in or sign up آپ کتاب کا معائنہ کر سکتے ہیں اور اپنے تجربات شیئر کرسکتے ہیں۔ دوسرے قارئین کتابوں کے بارے میں آپ کی رائے میں ہمیشہ دلچسپی رکھیں گے۔ چاہے آپ کو کتاب پسند ہے یا نہیں ، اگر آپ اپنے دیانتدار اور تفصیلی خیالات دیںگے تو لوگوں کو نئی کتابیں ملیںگی جو ان کے لئے صحیح ہیں۔ 1 Ischemic myocardial injuries after cardi... Marcela S. Oliveira; Elaine M. Floriano; Suleimy C... ISCHEMIC MYOCARDIAL INJURIES AFTER CARDIAC MALFORMATION REPAIR IN INFANTS MAY BE ASSOCIATED WITH OXIDATIVE STRESS MECHANISMS Marcela S. Oliveira, Elaine M. Floriano, Suleimy C. Mazin, Edson Z. Martinez, Walter V.A. Vicente, Luiz C. Peres, Marcos A. Rossi, Simone G. Ramos سال: 2011 زبان: english فائل: PDF, 3.90 MB آپ کے ٹیگز: 2 The Society for Cardiovascular Pathology... Bruce McManus THE SOCIETY FOR CARDIOVASCULAR PATHOLOGY CELEBRATING 25 DISRUPTIVELY EXCITING YEARS Bruce McManus سال: 2010 زبان: english فائل: PDF, 80 KB آپ کے ٹیگز: Cardiovascular Pathology 20 (2011) 139 – 145 Original Article Histopathologic correlates of myocardial improvement in patients supported by a left ventricular assist device Ana Maria Segura a,⁎, O.H. Frazier b , Zumrut Demirozu b , L. Maximilian Buja a,c a Department of Cardiovascular Pathology, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, USA Department of Cardiovascular Transplantation, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, USA c Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, Houston, TX, USA b Received 27 October 2009; received in revised form 11 January 2010; accepted 25 January 2010 Abstract Background: Left ventricular assist devices unload the failing heart and improve hemodynamic function and tissue architecture. In some patients improvement allows for left ventricular assist device removal. We retrospectively compared histologic features in patients who were weaned off left ventricular assist device support with those who remained on support without evidence of clinical remission. Methods: We graded left ventricular core samples taken at implantation on a scale we designed for evaluating severity and extent of fibrosis and hypertrophy. We correlated the grades with a computerized semiquantitative analysis of picrosirius-red and Masson's trichrome-stained sections. We evaluated interstitial (10×), perivascular (20×), and replacement (4×) fibrosis. Hypertrophy was assessed by myocyte diameter, cytoplasmic area, and nuclear/cytoplasmic ratio. Results: All patients (N=17) underwent left ventricular assist device implantation for heart failure. In eight patients improvement allowed left ventricular assist device removal. The groups did not differ in age (24.1 vs. 25 years, P=.4) or mean time on left ventricular assist device support (506 vs. 414 days, P=.24). All mean measures showed significantly less hypertrophy in the left ventricular assist device-removal group than in the nonremoval group, resp; ectively (cytoplasmic area, 58.00 vs. 77.18 μm2, P=.021; myocyte diameter, 20.32 vs. 25.35 μm, P=.004; nuclear/cytoplasmic ratio, 11.04 vs. 8.69, P=.053). Although not statistically significant, the left ventricular assist device-removal group tended toward less overall fibrosis than the nonremoval group (11.57 vs. 13.24, P=.214). Conclusions: Left ventricular assist device-removal patients had less hypertrophy and fibrosis overall than did nonremoval patients. These findings may help identify patients with a higher probability of left ventricular assist device removal and myocardial recovery. © 2011 Elsevier Inc. All rights reserved. Keywords: Heart-assist device; Hypertrophy; Myocardium; Myocyte; Remodeling; Transplantation 1. Introduction With the advent of cyclosporine, left ventricular assist devices (LVADs), originally developed for long-term support, have became clinically effective as a bridge to transplant [1,2]. Since the early 1900s, resting the heart has Presented at the meeting of the American Heart Association, Scientific Sessions 2008, November 10, 2008. Funding: none. Conflict of interest: none. ⁎ Corresponding author. Cardiovascular Pathology, Texas Heart Institute at St. Luke's Episcopal Hospital, PO Box 20345, MC 1-283 Houston, TX 77225-0345, USA. Tel.: +1 832 355 7202; fax: +1 832 355 6812. E-mail address: asegura@heart.thi.tmc.edu (A.M. Segura). 1054-8807/10/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2010.01.011 been the method of treatment for heart failure [3,4]. The LVAD is the most effective method currently available for resting the heart while allowing normal activity for the patient. Our group has reported on the histologic, anatomic, and physiologic improvements in the hearts of patients who were bridged to transplant in the early 1990s [5]. Unloading the failing heart initiates mechanisms and pathways that lead to beneficial changes in the cellular and tissue architecture of the heart and to improved hemodynamic function [6–8]. In some patients in whom the LVAD was removed because of infection or device failure, native cardiac function improved sufficiently to avoid subsequent device replacement or transplantation. However, this phenomenon has been studied prospectively in only a limited fashion [1,8–11]. 140 A.M. Segura et al. / Cardiovascular Pathology 20 (2011) 139–145 No clinical guidelines are currently available to reliably predict outcome in patients with LVADs. Although histologic features such as fibrosis and hypertrophy have been associated with deterioration of myocardial function, their usefulness as markers of clinical status has not been established. To quantify the extent and severity of fibrosis and hypertrophy, we developed a semiquantitative grading scale to help determine histologic features that may be useful in predicting clinical outcome. In this study, using both a semiquantitative grading scale and morphometric evaluation, we (a) evaluated histologic parameters at LVAD implantation in patients with clinical myocardial improvement who were weaned from mechanical support, (b) correlated the severity and extent of fibrosis and hypertrophy at implantation of the device with the clinical course, and (c) compared the histopathologic features of patients in whom myocardial function improved enough to allow device explantation with those who did not have significant clinical recovery and who remained on LVAD support or died. pus BX61). At low power (1.25×), we studied the overall amount of fibrosis on each slide. Perivascular fibrosis (10×) (Fig. 1A) was defined as the amount of fibrous tissue localized within 1 diameter of each vessel and was evaluated in all perivascular spaces of five randomly selected areas of each slide. Interstitial fibrosis (20×) was measured in five randomly selected areas of each slide. Replacement fibrosis (4×), defined as deposits of fibrous tissue that replaced myocytes, was studied by measuring the percentage of myocardial compromise in areas of replacement fibrosis (Fig. 1B). To assess hypertrophic changes, we studied three variables: myocyte diameter, myocyte area, and nuclear/ cytoplasmic (N/C) ratio. All measurements were obtained on at least 10 randomly selected myocytes in five sections of H&E-stained slides (20×). Myocyte diameter was obtained by measuring the length of a cross-sectional diameter perpendicular to the nucleus (Fig. 2). Nuclear/cytoplasmic ratio and myocyte area were measured by delineating the 2. Methods 2.1. Patients We studied patients with idiopathic cardiomyopathy who required LVAD implantation for heart failure at the Texas Heart Institute at St. Luke's Episcopal Hospital. Patients with ischemic cardiomyopathy were excluded. We studied two groups: those who showed sufficient echocardiographic and clinical improvement in native heart function to suggest weaning from mechanical support (LVAD-removal group) and a similar cohort of randomly selected patients who lacked evidence of echocardiographic improvement and who remained on support or died (nonremoval group). We retrospectively reviewed the data from the charts of all patients. The following information at the time of implantation and histologic specimen retrieval was recorded: age, gender, duration of heart failure, hemodynamic parameters, and type of LVAD. Both groups of patients (removal and nonremoval) were maintained on their regular heart failure therapy. 2.2. Histologic assessment We blindly evaluated biopsy specimens of the left ventricular apex taken at the time of LVAD implantation in all patients. Specimens were fixed in formaldehyde, embedded in paraffin, serially sectioned, and stained with hematoxylin and eosin (H&E). We designed a grading system (see below) to evaluate the presence and severity of interstitial, perivascular, and replacement fibrosis, and the severity of hypertrophy. The extent and severity of fibrosis were determined by a computerized quantitative analysis of positive Picrosirius red-stained areas and Masson's trichrome-stained slides (Microsuite Biological Suite, Olym- Fig. 1. Left ventricular core at implantation stained with Masson's trichrome (10×) showing (A) perivascular fibrosis extending into the interstitium and (B) replacement fibrosis with extensive fibrous tissue deposited in the interstitium replacing myocytes. A.M. Segura et al. / Cardiovascular Pathology 20 (2011) 139–145 141 replacement fibrosis. The fibrosis score ranged from 0 to 6, based on the combined score of interstitial/perivascular and replacement fibrosis: 0=no fibrosis, 1 to 2=mild, 3 to 4=moderate, and 5 to 6=severe. Computerized measurements defined mild as 0 to b15% fibrosis; moderate, 15% to 30%; and severe, N30%. The combined scores were correlated with the computerized measurements. The correlation between the histologic-based grading scale and computerized measurements was 80.41%. Hypertrophy findings were graded separately from fibrosis measurements. Overall, hypertrophy was graded on a scale of 0 to 3: 0=no hypertrophy, 1=mild, 2=moderate, and 3=severe. 2.4. Statistical analysis Fig. 2. Histologic section showing hypertrophy measurements (H&E, 20×). Myocyte diameter was obtained by computerized measurement of the length of a cross-sectional diameter perpendicular to the nucleus. cytoplasmic and nuclear borders of each myocyte and defining the percentage of each area. 2.3. Grading scale We used a grading scale based on the severity and extent of fibrosis and hypertrophy (Table 1, Fig. 3A–F). Fibrosis was defined histologically by adding the sum of the interstitial and perivascular fibrosis scores to the score for Histologic findings were compared between the two groups and were correlated with clinical parameters. Values of continuous variables are expressed as the mean±S.D. A P value b.05 was considered statistically significant for all analyses (SAS software). A nonparametric rank sum test was used to evaluate the relation of age, gender, left ventricular dimensions, and duration of heart failure with clinical recovery. 3. Results 3.1. Patients Table 1 Histologic-based grading scale for assessing interstitial, perivascular, and replacement fibrosis and hypertrophy Grading scale for fibrosis and hypertrophy Fibrosis Interstitial and Perivascular Fibrosis 0=Negative _____ 1=Perivascular _____ 2=Perivascular with extension to interstitium ______ a. focal ____ b. diffuse ____ 3=Encircling of individual myocytes ______ a. without perivascular fibrosis _____ b. with perivascular fibrosis _____ Replacement Fibrosis 0=Negative ______ 1=Minimal foci _____ 2=Occasional foci and small scars _____ 3=Extensive scarring _____ Grade _____ Grade _____ Interstitial and Perivascular Grade+Replacement Grade=Fibrosis Combined Score ____ Hypertrophy Grade _____ 0=Negative _____ 1=Occasional foci (mild) _____ 2=Multiple foci (moderate) _____ 3=Extensive, diffuse (severe) _____ The study population comprised 17 patients (eight patients in the LVAD-removal group and nine in the nonremoval group). In the nonremoval group, six patients remained on support and three patients died. The groups were paired by age (younger than 50 years old), type of device (HeartMate II), and etiology of heart failure (idiopathic cardiomyopathy). The LVAD-removal group did not differ significantly from the nonremoval group in age (24.12 vs. 25.0 years; P=.4), gender (six men and two women vs. eight men and one woman), or time on LVAD support (506 vs. 414 days; P=.24), respectively. In addition, hemodynamic parameters at baseline did not differ significantly between the two groups (Table 2). However, duration of heart failure was 10±15.8 months in the LVAD-removal group and 33±35.4 months in the nonremoval group (P=.05). Although the duration of heart failure differed significantly between the two groups, the range of heart failure duration overlapped (removal group, 1 to 48 months; nonremoval group, 2 to 107 months). 3.2. Fibrosis Less overall fibrosis was seen in the LVAD-removal group than in the nonremoval group (Fig. 4). Although the difference did not reach statistical significance, fibrosis of all types (perivascular, interstitial, and replacement) tended to be lower in patients who recovered sufficient myocardial 142 A.M. Segura et al. / Cardiovascular Pathology 20 (2011) 139–145 Fig. 3. Histologic sections showing stages according to the grading scale for fibrosis and hypertrophy. (A) Interstitial and perivascular fibrosis, Grade 1: Focal fibrosis predominantly surrounding vessels. (B) Interstitial and perivascular fibrosis, Grade 2b: Perivascular fibrosis with diffuse extension to the interstitial space. (C) Replacement fibrosis, Grade 3: Extensive deposition of fibrous tissue with replacement of myocardium. (D) Hypertrophy, Grade 1: Mild enlargement of cytoplasm and nuclei. (E) Hypertrophy, Grade 2: Multiple foci of nuclear and cytoplasmic enlargement, with moderate nuclear pleomorphism. (F) Hypertrophy, Grade 3: Severe myocyte enlargement with extensive nuclear hyperchromasia and pleomorphism. A.M. Segura et al. / Cardiovascular Pathology 20 (2011) 139–145 Table 2 Hemodynamic parameters at baseline in LVAD-removal patients and in those who remained on support (nonremoval) Age (years) Gender Duration of heart failure (months) Ejection fraction (%) LVEDD (cm) Pulmonary artery pressure (mmHg) PCWP (mmHg) Cardiac index (l/min) Removal (n=8) Nonremoval (n=9) P value 24.12±7.71 M=6, F=2 10±15.8 15.3±4.5 6.75±0.7 46.6±4.5 20.3±4.1 1.48±0.07 25.0±8.7 M=8, F=1 33±35.4 19.25±5.6 6.42±0.9 52±5.65 24.0±3.33 1.75±0.34 .414 .247 .05 .15 .28 .42 .067 .065 Data are presented as the mean±S.D. LVEDD, Left ventricular end diastolic diameter; PCWP, pulmonary capillary wedge pressure. function to allow pump removal than in those without improvement (Fig. 4). 3.3. Hypertrophy The cytoplasmic area and myocyte diameter were significantly smaller in the LVAD-removal patients than in the nonremoval patients (Fig. 5A,B). Furthermore, the nucleus/cytoplasm ratio was larger in specimens from the LVAD-removal patients than in those from nonremoval patients (Fig. 5C). 3.4. Grading scale correlation We observed a significant correlation (r=80.4%) between our grading scale and the computerized quantitative histologic measurements of overall fibrosis. 143 4. Discussion In our study, patients with sufficient clinical improvement for LVAD removal had less severe alterations in myocardial structure in the initial histologic specimen at the time of implantation than did patients who remained on support and required transplantation. Measures of hypertrophy such as cytoplasmic area and myocyte diameter were significantly smaller and the nucleus/cytoplasm ratio was larger in patients who were weaned than in patients who required continued support. In addition, we saw a trend toward less overall fibrosis in patients in whom the LVAD was removed. All types of fibrosis (perivascular, interstitial, and replacement) were seen more frequently in patients without functional improvement than in those who recovered function. Improvement in native cardiac function should not be anticipated in patients in whom functional myocytes have been replaced with extensive fibrosis; however, viable myocytes, despite their abnormal histologic appearance commensurate with heart failure, may retain the ability to recover their functionality. On the basis of these findings, we hypothesize that the extent and severity of hypertrophy and fibrosis in left ventricular core samples taken at the time of LVAD implantation may help identify patients who have the potential to improve sufficiently to allow removal of mechanical support and remain on successful medical management. Patients who respond better to ventricular unloading generally have less fibrosis (especially replacement fibrosis) and hypertrophy at the time of LVAD implantation. Our grading scale designed to evaluate histologic findings correlated well with computerized measurements of fibrosis. Using the scale to evaluate the types of fibrosis seen on H&E Fig. 4. Quantitative computer analysis. Comparison of fibrosis in myocardial tissue in patients in whom clinical improvement was sufficient to allow LVAD removal and in patients without clinical improvement who continued on mechanical support (nonremoval). 144 A.M. Segura et al. / Cardiovascular Pathology 20 (2011) 139–145 Fig. 5. (A) Comparison of myocyte diameter between the removal and nonremoval groups. (B) Comparison of cytoplasmic area between the removal and nonremoval groups. (C) Comparison of the N/C ratio between the two groups. slides allowed us to quantitatively establish the extent and severity of fibrosis. We were then able to accurately assess myocardial structural damage in the initial sample of patients requiring ventricular support. Cardiac remodeling is a compensatory response to a noxious stimulus of variable and frequently unknown etiologies. Characterized by altered genomic expressions, cardiac remodeling results in molecular, cellular, biochemical, and structural changes. These changes are manifested clinically by modifications in the size, shape, and function of the heart. At the cellular level, cardiac remodeling alters cardiomyocytes, fibroblasts, and the extracellular matrix [12]. Myocyte hypertrophy and fibrosis are the crucial morphological alterations in the remodeling process. Hyper- trophy, or cardiomyocyte growth in thickness and length, is caused by pressure and volume overload [13]. Cardiac hypertrophy due to hemodynamic overload is associated with increased deposition of extracellular matrix and proliferation of cardiac fibroblasts. The accumulation of fibrous tissue at the sites of cardiomyocyte necrosis is called replacement fibrosis. It differs from interstitial fibrosis, which is reactive in origin and initially surrounds intramyocardial coronary arteries but eventually extends into the contiguous interstitial space [14]. During the fibrotic process the accumulation of types I and III collagen reduces myocardial distensibility, leading to diastolic and systolic dysfunction. Significant ventricular dilatation can occur, perhaps related to an increase in collagen synthesis that exceeds collagen degradation, or when the change in collagen cross-linking alters the interactions of the extracellular matrix and myocytes [15,16]. The duration of heart failure symptoms correlates with the extent of fibrosis and hypertrophic changes in cardiomyocytes. Previous studies have shown that patients who have had a longer duration of heart failure symptoms have more severe alterations on histologic examination of left ventricular specimens [17]. The clinical determination of the exact duration of heart failure is often difficult because some patients, especially young ones, do not manifest symptoms in spite of marked cardiac enlargement and histologic hallmarks of cardiac deterioration in advanced stages of heart failure. Moreover, patients with an acute onset of severe heart failure who undergo early LVAD implantation may have had previous symptoms without medical consultation. Prolonged LVAD support for patients with end-stage heart failure may lead to structural reverse remodeling, which may be accompanied by functional improvement [18–22]. During LVAD support, left ventricular mass decreases and diastolic chamber properties, such as the relationship of end-diastolic pressure to volume, return to normal [23]. Chronic mechanical unloading can cause cellular hypertrophy to regress and cell size and shape to return toward normal [5,6]. Although fibrosis can lessen after LVAD support, changes in myocyte size account for most of the reduction in left ventricular mass [24]. Several studies have reported a reduction in collagen in patients after LVAD support [25,26]. However, others have reported an increase in cross-linking of left ventricular collagen and an increase in the ratio of collagen type I to III, leading to increased myocardial stiffness [10,27,28]. Despite the beneficial effects of ventricular unloading at the cellular and clinical levels, only a subgroup of patients has tolerated LVAD explantation without transplantation [29,30]. A possible explanation for insufficient functional improvement in most patients may be related to the response in the cardiac extracellular matrix, especially the fibrotic response and altered patterns of collagen cross-linking [31]. Currently, there are no reliable markers to predict sustained improvement and recovery with mechanical support. In this study, we attempt to assess histologic parameters obtained at A.M. Segura et al. / Cardiovascular Pathology 20 (2011) 139–145 the time of LVAD implant to identify patients in whom mechanical circulatory support may be safely discontinued. In conclusion, we have shown that fewer structural changes are found in recovered patients than in those who require continued ventricular support. Specifically, LVADremoval patients had less hypertrophy and fibrosis overall than did nonremoval patients. Although the number of patients in our study who recovered sufficient function to discontinue support was small, we believe histopathology at the time of implantation, in correlation with clinical parameters, may help identify patients with a higher probability of LVAD removal and myocardial recovery. 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