Reduced Progression of Cardiac Allograft Vasculopathy with Routine Use of Induction Therapy with Basiliximab / Redução da Progressão da Doença Vascular do Enxerto Cardíaco com o Uso Rotineiro da Terapia de Indução com Basiliximab

AbstractIntroduction:Cardiac allograft vasculopathy (CAV) is a major limitation for long-term survival of patients undergoing heart transplantation (HT). Some immunosuppressants can reduce the risk of CAV.Objectives:The primary objective was to evaluate the variation in the volumetric growth of the intimal layer measured by intracoronary ultrasound (IVUS) after 1 year in patients who received basiliximab compared with that in a control group.Methods:Thirteen patients treated at a single center between 2007 and 2009 were analyzed retrospectively. Evaluations were performed with IVUS, measuring the volume of a coronary segment within the first 30 days and 1 year after HT. Vasculopathy was characterized by the volume of the intima of the vessel.Results:Thirteen patients included (7 in the basiliximab group and 6 in the control group). On IVUS assessment, the control group was found to have greater vessel volume (120–185.43 mm3 vs. 127.77–131.32 mm3; p = 0.051). Intimal layer growth (i.e., CAV) was also higher in the control group (27.30–49.15 mm3 [∆80%] vs. 20.23–26.69 mm3[∆33%]; p = 0.015). Univariate regression analysis revealed that plaque volume and prior atherosclerosis of the donor were not related to intima growth (r = 0.15, p = 0.96), whereas positive remodeling was directly proportional to the volumetric growth of the intima (r = 0.85, p < 0.001).Conclusion:Routine induction therapy with basiliximab was associated with reduced growth of the intima of the vessel during the first year after HT.

ResumoFundamento:A doença vascular do enxerto (DVE) constitui uma grande limitação de sobrevida a longo prazo de pacientes submetidos a transplante cardíaco (TxC). Alguns imunossupressores diminuem o aparecimento da DVE.Objetivos:O principal objetivo foi avaliar, através de ultrassonografia intracoronária (USIC), a variação do crescimento volumétrico da camada íntima e comparar, após um ano, o grupo que recebeu basiliximab com um grupo de controle.Métodos:Treze pacientes de um único centro foram analisados retrospectivamente de 2007 a 2009. As análises foram feitas através de USIC, medindo-se o volume de um segmento coronariano nos primeiros 30 dias e um ano após o TxC. A vasculopatia foi caracterizada pelo volume da camada íntima do vaso.Resultados:O estudo incluiu 13 pacientes (7 no grupo com o basiliximab e 6 no grupo de controle). A análise por USIC revelou que o grupo de controle apresentou maior crescimento volumétrico do vaso (131,32 a 127,77 mm3 x 120 a 185,43 mm3 p = 0,051). O crescimento da camada íntima (CCI) também foi maior no grupo de controle [Basiliximab: 20,23 a 26,69 mm3 (∆ 33%); Controle: 27,30 a 49,15 mm3(∆ 80% p = 0,015)]. De acordo com a regressão univariada, o volume da placa aterosclerótica prévia do doador não teve relação com o crescimento da íntima (r = 0,15, p = 0,96), enquanto que o remodelamento positivo do vaso foi diretamente proporcional ao crescimento da íntima (r = 0,85, p < 0,001).Conclusão:A terapia de indução de rotina com basiliximab está associada à redução do crescimento da camada íntima do vaso no primeiro ano após o transplante cardíaco.

Reduced progression of cardiac allograft vasculopathy with routine use of induction therapy with basiliximab.

INTRODUCTION: Cardiac allograft vasculopathy (CAV) is a major limitation for long-term survival of patients undergoing heart transplantation (HT). Some immunosuppressants can reduce the risk of CAV. OBJECTIVES: The primary objective was to evaluate the variation in the volumetric growth of the intimal layer measured by intracoronary ultrasound (IVUS) after 1 year in patients who received basiliximab compared with that in a control group. METHODS: Thirteen patients treated at a single center between 2007 and 2009 were analyzed retrospectively. Evaluations were performed with IVUS, measuring the volume of a coronary segment within the first 30 days and 1 year after HT. Vasculopathy was characterized by the volume of the intima of the vessel. RESULTS: Thirteen patients included (7 in the basiliximab group and 6 in the control group). On IVUS assessment, the control group was found to have greater vessel volume (120-185.43 mm3 vs. 127.77-131.32 mm3; p = 0.051). Intimal layer growth (i.e., CAV) was also higher in the control group (27.30-49.15 mm3 [∆80%] vs. 20.23-26.69 mm3[∆33%]; p = 0.015). Univariate regression analysis revealed that plaque volume and prior atherosclerosis of the donor were not related to intima growth (r = 0.15, p = 0.96), whereas positive remodeling was directly proportional to the volumetric growth of the intima (r = 0.85, p < 0.001). CONCLUSION: Routine induction therapy with basiliximab was associated with reduced growth of the intima of the vessel during the first year after HT.

Regenerative potential of low-concentration SDS-decellularized porcine aortic valved conduits in vivo.

The aims of this study were to determine the functional biocompatibility of low-concentration SDS-decellularized porcine aortic roots in vivo. A previously developed process was modified for 9- and 15-mm-diameter aortic roots to facilitate implantation into the porcine abdominal aorta (n=3) and juvenile sheep right ventricular outflow tract (n=7), respectively. Native allogeneic aortic roots were used as controls. Acellular porcine roots explanted from pigs at weeks were largely repopulated with stromal cells of appropriate phenotype, and there was evidence that macrophages were involved in the regenerative process. Native allogeneic roots were subject to a classic allograft rejection response. Acellular porcine roots explanted from sheep at 6 months showed evidence of appropriate cellular repopulation, again with evidence of a role for macrophages in the regenerative process. There was some degree of calcification of two of the explanted acellular roots, likely due to incomplete removal of DNA before implantation. Native allogeneic ovine roots were subject to a classic allograft rejection response involving T cells, which resulted in overtly calcified and damaged tissues. The study highlighted (1) the importance of removal of DNA from acellular porcine valved roots to avoid calcification and (2) a role for macrophages in the regeneration of low-concentration SDS-decellularized aortic roots, as has been reported for other acellular biological extracellular matrix scaffolds.

Long-term results of the Ross operation: an 18-year single institutional experience.

OBJECTIVES: The purpose of the study was to assess the 18-year outcome of the Ross operation (RO), with emphasis on survival, reoperations, and late function of the pulmonary autografts (PAs) and the right-sided pulmonary allografts. METHODS: Between May 1995 to July 2013, 414 patients with a mean age (mean ± standard deviation) of 30.8 ± 13.1 years were submitted to an RO with the root replacement (n = 356) or the inclusion (n = 58) technique. The most prevalent aetiology was bicuspid valve (n = 206, 49.8%). Patients were divided in four groups depending on the type of allograft used on the right side. The mean follow-up was 8.2 ± 5.2 years and was 97.7% complete. In addition to longitudinal outcomes determined by means of the Kaplan-Meier analysis, log-rank test and Cox regression analysis were used to identify predictors of valve failure. RESULTS: The early mortality rate was 2.7% and the late survival rate was 89.3% at 15 years, similar to an age- and sex-matched population. There were 22 reoperations on the PA (90.7% freedom at 15 years) and 15 on the pulmonary allografts (92.5% freedom at 15 years). The freedom rate from more than mild aortic insufficiency (AI) was 73.1% at 15 years. Thirty-three patients presented with a late root diameter >45 mm, corresponding to a freedom rate of 72.4% at 15 years. Patients with AI and a dilated annulus, especially males, are at greater risk for these complications. Among the right-sided allografts, fresh decellularized allografts showed significantly superior freedom from structural valve dysfunction. CONCLUSIONS: The RO was associated with excellent long-term survival and low incidence of reoperations up to 15 years. Male patients with AI and dilated annulus are at increased risk for late insufficiency and root dilatation. Fresh decellularized allografts presented the best results for reconstruction of the right ventricular outflow tract.

Aortic valve replacement with the Cardioprotese Premium bovine pericardium bioprosthesis: four-year clinical results.

OBJECTIVES: This study reports the initial clinical and echocardiographic results of the Premium bioprosthetic aortic valve up to 4 years of follow-up. METHODS: Between October 2007 and July 2011, 121 consecutive patients were submitted for aortic valve replacement with the Premium bioprosthetic valve. The mean age was 68 ± 9 years and 64 patients were males. The patients were periodically evaluated by clinical and echocardiographic examinations. The mean follow-up was 21 months (min = 2, max = 48), yielding 217 patients/year for the analysis. RESULTS: The hospital mortality was 8%. Late survival at 3 years was 89% (95% CI: 81.9-93.3%), and 80% of the patients were in NYHA functional class I/II. The rates of valve-related complications were low, with a linearized incidence of 0.9%/100 patients/year for thromboembolic complications, 0% for haemorrhagic events and 0.9%/100 patients/year of bacterial endocarditis. There was no case of primary structural valve dysfunction. The mean effective orifice area was 1.61 ± 0.45 cm(2); mean gradient 13 ± 5 mmHg and peak gradient 22 ± 9 mmHg. Significant patient-prosthesis mismatch was found in only 11% of the cases. CONCLUSIONS: The Premium bioprosthetic aortic valve demonstrated very satisfactory clinical and echocardiographic results up to 4 years, similar to other commercially available, third-generation bioprosthetic valves.

The early and midterm function of decellularized aortic valve allografts.

BACKGROUND: This study evaluates the early and midterm results of decellularized aortic valve allografts (DAVA) as an aortic valve replacement. METHODS: Between October 2005 and February 2010, 41 patients, 28 of whom were male, with a median age of 34 years (range, 0.1 to 71), had aortic valve replacement with DAVA. Decellularization was obtained with a 0.1% sodium dodecyl sulfate solution. Postoperative evaluation was performed with serial echocardiograms, magnetic resonance imaging, and multislice computed tomography studies to evaluate valve hemodynamics, allograft conduit dimensions, and calcification scores. RESULTS: There were 3 early deaths and 1 late death, with a mean follow-up of 19 months (range, 1 to 53). There was 1 reoperation due to a failed mitral valve repair. By echocardiography in all patients, the median immediate postoperative peak gradient was 7 mm Hg (range, 1 to 26 mm Hg), and at last follow-up it was 4 mm Hg (range, 1 to 16 mm Hg); valvular regurgitation was graded as none or trivial in all but 1 patient, who had a regurgitation graded as mild to moderate. By magnetic resonance imaging (n = 4), mean root dimensions were stable at the annulus (24 mm), sinus of Valsalva (33 mm), and sinotubular junction (28 mm). By computed tomography (n = 22), there was only discrete conduit calcification (median calcium score 63 Hounsfield units [HU]; range, 0 to 894 HU) to 3 years of follow-up. Conduit biopsy in the patient who underwent reoperation demonstrated well-preserved wall structure, absence of calcification, and limited in vivo host repopulation. CONCLUSIONS: The early and midterm results with DAVA demonstrated stable structural integrity, low rate of calcification, and adequate hemodynamics. Although longer periods of observation are necessary, DAVA appears to be a promising alternative for aortic valve replacement in selected patients.

Operação de Ross com homoenxertos valvares decelularizados: resultados de médio prazo / Ross Operation with decelularized pulmonary allografts: medium-term results

OBJETIVO: Avaliar os resultados de médio prazo do uso de homoenxertos decelularizados na Operação de Ross. MÉTODOS: Entre janeiro de 2003 e fevereiro de 2007, 68 pacientes foram submetidos à Operação de Ross com homoenxertos decelularizados. Quarenta e oito pacientes eram do sexo masculino, com idade media de 30,3±11,2 anos. A decelularização foi feita com Ácido Deoxicólico (DOA), em 35 casos, e com Dodecilsulfato de Sódio (SDS), em 33. Para a comparação dos gradientes, foram selecionados 68 pacientes pareados pela idade, e que usaram homoenxertos criopreservados. Todos os pacientes realizaram ecocardiograma antes da alta e estão sendo avaliados anualmente. Oito pacientes tiveram controle por ressonância nuclear. Em dois pacientes reoperados, foi possível fazer análise histológica de um segmento do conduto pulmonar. RESULTADOS: Houve um (1,4 por cento) óbito imediato. Na evolução tardia, houve duas reoperações e um óbito. Os gradientes imediatos variaram de 4 a 29mmHg (m=10,3±5,5), e apresentaram elevação para 16,5± 12,2mmHg (min= 4, max = 45) aos 24 meses. Quando comparados com o grupo criopreservado, não houve diferenças significativas. Entretanto, houve tendência a melhores resultados em homoenxertos decelularizados com SDS após 12 meses de evolução. A análise histológica revelou reendotelização e repovoamento parcial da camada média com células autógenas. Não houve insuficiência pulmonar progressiva. Os dados de ressonância magnética demonstraram menor tendência de retração dos condutos decelularizados. CONCLUSÕES: O uso de homoenxertos decelularizados foi seguro, com bons resultados até quatro anos de evolução. Houve tendência a menores gradientes tardios nos homoenxertos decelularizados com SDS após 12 meses.

OBJECTIVE: To evaluate the medium-term results (4 years) of decelularized allografts during Ross Operation. METHODS: From January 2003 to February 2007, 68 patients underwent Ross Operation with decelularized allografts. Forty eight were male and the mean age was 30.3±11.2 years. Decelularization was done with deoxicolic acid (DOA) in 35 cases and with sodium dodecylsulfate (SDS) in 33. For comparison of the gradients, 68 patients with cryopreserved allografts and matched for age were selected. All patients had a control echo before hospital discharge and annually thereafter. In addition, eight patients had MRI studies. In two patients, samples of the conduit wall were analyzed by histological analysis. RESULTS: There was one (1.4 percent) early death. In the late follow-up, there were two reoperations for endocarditis and one late death. The early gradients varied between 4 29 mmHg (m= 10.3± 5.5mmHg) and exhibited an increase to 16.5±12.2 mmHg (min=4, max=45) at 24 months postoperatively. There were no significant differences when compared to the cryopreserved group. There was, however, a tendency towards lesser gradients in the SDS decelularized group after 12 months. Histological analysis revealed partial reendothelization and progressive repopulation of the tunica media with autogenous cells. There was no progressive pulmonary insufficiency. The MRI results showed a lesser tendency to shrinkage in the decelularized conduits. CONCLUSIONS: The use of decelularized allografts was safe and with good medium-term results up to 4 years. There was a tendency to lower late gradients in the SDS decelularized allografts after 12 months.

Ross Operation with decellularized pulmonary allografts: medium-term results.

OBJECTIVE: To evaluate the medium-term results (4 years) of decellularized allografts during Ross Operation. METHODS: From January 2003 to February 2007, 68 patients underwent Ross Operation with decellularized allografts. Forty eight were male and the mean age was 30.3+/-11.2 years. Decellularization was done with deoxicolic acid (DOA) in 35 cases and with sodium dodecylsulfate (SDS) in 33. For comparison of the gradients, 68 patients with cryopreserved allografts and matched for age were selected. All patients had a control echo before hospital discharge and annually thereafter. In addition, eight patients had MRI studies. In two patients, samples of the conduit wall were analyzed by histological analysis. RESULTS: There was one (1.4%) early death. In the late follow-up, there were two reoperations for endocarditis and one late death. The early gradients varied between 4 29 mmHg (m= 10.3+/- 5.5 mmHg) and exhibited an increase to 16.5+/-12.2 mmHg (min=4, max=45) at 24 months postoperatively. There were no significant differences when compared to the cryopreserved group. There was, however, a tendency towards lesser gradients in the SDS decellularized group after 12 months. Histological analysis revealed partial reendothelization and progressive repopulation of the tunica media with autogenous cells. There was no progressive pulmonary insufficiency. The MRI results showed a lesser tendency to shrinkage in the decellularized conduits. CONCLUSIONS: The use of decellularized allografts was safe and with good medium-term results up to 4 years. There was a tendency to lower late gradients in the SDS decellularized allografts after 12 months.

Eficácia do AlCl3 e etanol na prevenção da calcificação de fragmentos da parede aórtica porcina fixados em GDA / Efficacy of AlCl3 and ethanol in the prevention of calcification of fragments of porcine aortic wall fixed in GDA

OBJETIVO: Avaliar a eficácia do cloreto de alumínio, isoladamente ou em associação com o etanol, na prevenção da calcificação e da resposta inflamatória de fragmentos de parede aórtica porcina fixada em glutaraldeído (GDA), implantados no tecido subcutâneo de ratos jovens. MÉTODO: Utilizaram-se 15 ratos da linhagem Sprague-Dawley, em cujas telas subcutâneas foram implantados fragmentos de parede aórtica porcina, submetidos a três diferentes métodos de tratamento [grupos: I (GDA), II (GDA+alumínio), III (GDA+etanol+alumínio)]. Os explantes foram realizados com 15, 30 e 60 dias após as operações. Foram realizadas análises histológicas pelas colorações de hematoxilina & eosina (HE) e de alizarina, nos pHs de 4,2 e 7,0, e a dosagem de cálcio feita por espectroscopia de absorção atômica. RESULTADOS: Pelo HE, constatou-se que a matriz extracelular das paredes aórticas ficaram melhor preservadas nos explantes do grupo III. A intensidade da reação inflamatória intensa foi menor nesse grupo. Pela alizarina pH 4,2, o grupo II e III tiveram menores índices de calcificação comparado ao controle. Pela alizarina pH 7,0, o grupo III teve menor índice de calcificação comparado aos grupos I e II. Pela espectroscopia de absorção atômica, os níveis de cálcio foram semelhantes para os grupos II e III, mas significativamente menores do que os do grupo I. CONCLUSÃO: O tratamento com cloreto de alumínio diminuiu a calcificação dos fragmentos de parede aórtica porcina. O uso combinado do etanol com cloreto de alumínio foi ainda mais eficiente em inibir a calcificação, e também em diminuir a reação inflamatória.

OBJECTIVE: To evaluate the efficiency of aluminum chloride in isolation or associated with ethanol to prevent calcification and inflammatory reaction with fragments of porcine aortic wall fixed in glutaraldehyde (GDA) and subdermally implanted in young rats. METHOD: Fifteen Sprague-Dawley rats were studied. Three fragments of porcine aortic wall were implanted in the subdermal tissue. The fragments were previously subjected to three different methods of treatment: I (GDA), II (GDA + aluminum), III (GDA + ethanol + aluminum). Explantation was performed after fifteen, thirty and sixty days. Histological analysis was achieved using hematoxylin & eosin (HE) and alizarin-red at pHs of 4.2 and 7.0. Calcium content was determined by atomic absorbance spectroscopy. RESULTS: HE and alizarin red staining showed that the aortic wall extracellular matrix was best preserved in the fragments of Group III. The intensity of the inflammatory reaction was lower in this group. When stained with alizarin red at pH 4.2, Groups II and III had lower degrees of calcification compared with Group I. With alizarin red staining at pH 7.0, Group III demonstrated less calcification compared with Groups I and II. Atomic absorbance spectroscopy showed similar calcium levels for both Groups II and III, but significantly less than in Group I. CONCLUSION: Treatment with aluminum chloride inhibits calcification of fragments of aortic wall after implantation and reduces inflammatory reaction. The combined use of ethanol with aluminum chloride is more efficient to inhibit calcification and also to diminish inflammatory reaction.

Immunological and echocardiographic evaluation of decellularized versus cryopreserved allografts during the Ross operation.

OBJECTIVE: Compare the immunological and echocardiographic data of decellularized versus cryopreserved allografts used for RVOT reconstruction during Ross operation. METHODS: From 16/01/03 thru 07/10/03, 20 Ross operations were performed using decellularized (n=11) or cryopreserved (n=9) allografts. Echocardiography was done at discharge, 1, 3, 6 and 12 months and annually thereafter. Samples for determination of antibodies against HLA class I and II were obtained preoperatively and at days 5, 10, 30, 90 and 180 postoperatively. These samples were tested by the ELISA method in LAT-M dishes (unspecific) for identification of circulating antibodies and the results expressed as mean sample values (Is=DO/cutoff). If positive, LAT-E (specific) was performed and PRA levels determined. RESULTS: There was no mortality. Cryopreserved allografts showed marked Is values elevations for class I and II antibodies which started at the first month and remained elevated up to 6 months. In contrast, of the patients receiving decellularized allografts, seven remained negative, two patients had only marginal elevation of class I antibodies and two patients showed abnormal elevations of PRA levels. This response happened earlier than in the cryopreserved group, starting on the 5th postoperative day and has returned to baseline levels in one case. Echocardiography showed mild, but significant, elevation of gradients in cryopreserved valves but none in the decellularized. CONCLUSIONS: Decellularized allografts had normal function up to 18 months and showed important reduction of the immunogenic response when compared to cryopreserved valves.

Comparison of cryopreserved homografts and decellularized porcine heterografts implanted in sheep.

This study evaluated cryopreserved homografts (Group 1) and porcine heterografts decellularized with deoxicholic acid (Group 2), implanted in the right ventricular outflow tract of juvenile sheep. Two groups with four animals in each were used and all animals survived with good outcome. Animals were sacrificed 90 or more days after surgery (90-150 days). On the third and fifth postoperative months they were submitted to echocardiographic examination with normal function and appearance observed for both groups. Explants were evaluated through histological analysis, atomic spectrophotometry and radiological examination. Calcium content was higher in the cusps of cryopreserved homografts, despite an otherwise similar macroscopic appearance between grafts of both groups. Decellularized heterografts were progressively repopulated by autologous cells suggesting some regenerative ability and longer durability than conventional homografts.

Estudo experimental com heteroenxertos valvares descelularizados: a prótese do futuro / Experimental study with deccelularized porcine heterografts: the prosthesis of the future

OBJETIVO: Avaliar, comparativamente, o comportamento de homoenxertos valvares criopreservados e de heteroenxertos descelularizados implantados na via de saída do ventrículo direito de carneiros jovens, assim como relatar a experiência clínica inicial com homoenxertos descelularizados em pacientes submetidos à operação de Ross. MÉTODO: No grupo A, foram implantados quatro homoenxertos pulmonares criopreservados e no Grupo B, quatro heteroenxertos porcinos valvares descelularizados com ácido deoxicólico. Em cada grupo, dois animais foram sacrificados no 3º mês e dois no 5º mês de pós-operatório. As peças foram avaliadas macroscopicamente e por radiografias, além de exame microscópico com colorações HE, Tricrômico de Mallory e Sirius Red. A experiência clínica com quatro pacientes submetidos à operação de Ross com emprego de homoenxertos valvares descelularizados é relatada. RESULTADOS: Todos os animais sobreviveram. Os ecocardiogramas demonstraram boa função valvar nos dois grupos. Embora as cúspides valvares em ambos os grupos tivessem aspecto macroscópico normal, a mensuração de cálcio e o estudo radiológico demonstraram início de calcificação focal nos homoenxertos criopreservados, mas não nos heteroenxertos descelularizados. Esses achados foram confirmados por exames microscópicos. Os homoenxertos criopreservados demonstraram perda de sua celularidade, enquanto que os heteroenxertos descelularizados demonstraram repopulação progressiva da matriz colágena com fibroblastos, assim como reendotelização. Os quatro pacientes operados tiveram evolução pós-operatória imediata satisfatória, com função normal dos homoenxertos. CONCLUSÕES: Heteroenxertos valvares descelularizados foram progressivamente repopulados por células autógenas e exibiram mínima tendência à calcificação no modelo estudado. Esses resultados sugerem que homoenxertos descelularizados possam ter alguma capacidade regenerativa e com isso ter durabilidade superior aos homoenxertos criopreservados convencionais.