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BACKGROUND: Cardiac allograft vasculopathy (CAV) assessment post-heart transplantation (HT) typically relies on invasive coronary angiography (ICA). However, cardiac computed tomography angiography (CCTA) is emerging as a promising alternative due to its potential benefits in economic, safety, and logistical aspects. This study aimed to evaluate the impact of a CCTA program on these aspects in CAV surveillance post-HT. METHODS: A retrospective single-center study was conducted between March 2021 and February 2023, involving HT patients who underwent either CCTA or ICA. RESULTS: Among 260 patients undergoing CAV surveillance, 115 (44.2%) patients underwent CCTA, and 145 (55.8%) patients underwent ICA. The CCTA group showed incurred lower overall costs (p â< â0.0001) and shorter hospitalization times (p â< â0.0001) compared to the ICA group. In terms of safety, CCTA surveillance required significantly lower contrast volumes (p â< â0.0001) and lower effective doses (p â= â0.03). CONCLUSION: CCTA emerges as a safe and cost-effective non-invasive alternative for CAV surveillance post-HT, outperforming ICA in terms of safety, logistical aspects, and economic burden.
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Vasculitides are diseases that can affect any vessel. When cardiac or aortic involvement is present, the prognosis can worsen significantly. Pathological assessment often plays a key role in reaching a definite diagnosis of cardiac or aortic vasculitis, particularly when the clinical evidence of a systemic inflammatory disease is missing. The following review will focus on the main histopathological findings of cardiac and aortic vasculitides.
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Vasculitis , Humanos , Vasculitis/patología , Vasculitis/diagnóstico , Pronóstico , Aorta/patologíaRESUMEN
BACKGROUND: Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. We collected clinical, genetic and laboratory data of seven cases of biopsy-proven renal involvement by WM managed at our academic center and focused on three cases we judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options. CASE: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. In our series AL Amyloidosis (n = 3/7) and tubulo-interstitial infiltration by lymphoma cells (n = 3/7) were the two more represented entities. BTKi did not seem to improve renal function (Case 1), while bortezomib-based regimens demonstrated a beneficial activity on the hematological and organ response, even when used as second-line therapy after chemoimmunotherapy (Case 3) and also with coexistence of anti-MAG neuropathy (Case 2). In case of poor response to bortezomib, standard chemoimmunotherapy (CIT), such as rituximab-bendamustine, represents an effective option (Case 1, 6, and 7). In our series, CIT generates durable responses more frequently in cases with amyloidogenic renal damage (Case 1, 5, and 7). CONCLUSION: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. Studies with higher numerosity are needed to better clarify the pathological and clinical features of renal involvement during WM and to determine the potential benefit of different therapeutic regimens according to the histopathological subtypes.
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Macroglobulinemia de Waldenström , Humanos , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/patología , Macroglobulinemia de Waldenström/complicaciones , Macroglobulinemia de Waldenström/tratamiento farmacológico , Masculino , Anciano , Femenino , Persona de Mediana Edad , Riñón/patología , Biopsia , Bortezomib/administración & dosificación , Bortezomib/uso terapéuticoRESUMEN
BACKGROUND: Thrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical thrombectomy, estimate the age and organization of thrombi, and evaluate associations with the use of thrombolysis, antiplatelets, and heparin. METHODS: This retrospective observational study involved 72 samples (44 from cerebral and 28 coronary arteries), which were stained with hematoxylin and eosin, anti-NE (neutrophil elastase) antibody, and anti-histone H2B (histone H2B) antibody, representing different components in NET formation, all detectable during the later stages of NETosis, for histochemical and digital quantification of NET content. The histological and morphological evaluations of the specimens were correlated, through univariate and mediation analyses, with clinical information and therapy administered before intervention. RESULTS: The results demonstrated that the composition of cerebral and coronary thrombi differs, and there were significantly more lytic cerebral thrombi than coronary thrombi (66% versus 14%; P=0.005). There was a considerably higher expression of NETs in the cerebral thrombi as testified by the higher expression of H2B (P=0.031). Thrombolysis was remarkably associated with higher NE positivity (average marginal effect, 6.461 [95% CI, 0.7901-12.13]; P=0.02555), regardless of the origin of thrombi. There was no notable association between the administration of antiaggregant therapy/heparin and H2B/NE amount when adjusted for the thrombus location. Importantly, the age of the thrombus was the only independent predictor of NET content without any mediation of the thrombolytic treatment (P=0.014). CONCLUSIONS: The age of the thrombus is the driving force for NET content, which correlates with impaired clinical outcomes. The therapy that is currently administered does not modify NET content. This study supports the need to investigate new pharmacological approaches added to thrombolysis to prevent NET formation or enhance their disruption, such as recombinant human DNase I (deoxyribonuclease I).
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Trampas Extracelulares , Trombosis , Humanos , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Trombosis/tratamiento farmacológico , Trombosis/metabolismo , Histonas/metabolismo , Terapia Trombolítica , HeparinaRESUMEN
The utilization of kidneys from donors with acute kidney injury (AKI) is often limited by unpredictable post-transplantation outcomes. The aim of our study was to identify protein mediators implicated in either recovery or failure of these organs. Forty kidney biopsies from donors with (20) and without AKI (20) were selected and then subdivided according to the post-transplant outcome defined as a threshold of 45 ml/min for the eGFR at 1 year from transplantation. Tissue homogenates were analysed by western blot to assess how the levels of 17 pre-selected proteins varied across the four groups. Samples from AKI kidneys with a poor outcome showed a fourfold increase in the levels of PPARg and twofold reduction of STAT1 compared to the other groups (p < 0.05). On the contrary, antioxidant enzymes including TRX1 and PRX3 were increased in the AKI kidneys with a good outcome (p < 0.05). An opposite trend was observed for the detoxifying enzyme GSTp which was significantly increased in the AKI group with poor versus good outcome (p < 0.05). The importance of lipid metabolism (PPARg) and inflammatory signals (STAT1) in the function recovery of these kidneys hints to the therapeutical targeting of the involved pathways in the setting of organ reconditioning.
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Lesión Renal Aguda , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , PPAR gamma , Supervivencia de Injerto , Donantes de Tejidos , Riñón/patología , Lesión Renal Aguda/patología , Biopsia , Estudios RetrospectivosRESUMEN
A 45 year old male obese patient with a previous history of repaired congenital heart disease developed worsening heart failure making heart transplantation listing mandatory. Unfortunately, due to his anthropometric measures, the search for a suitable brain-dead donor was unsuccessful. For this reason, he accepted to be enrolled in the controlled donation after circulatory death (cDCD) program. According to the Italian Law regulating death declaration after cardiac arrest (no-touch period of 20 minutes-one of the longest in the world), we faced a 34 minute cardiac asystole, after which the heart was recovered through a thoraco-abdominal normothermic regional perfusion excluding the epiaortic vessels. The heart was then preserved by means of cold static storage. Heart transplantation was performed successfully without any signs of primary graft failure. Postoperative endomyocardial biopsies were negative for acute cellular and antibody-mediated rejection. Furthermore, echocardiographic and cardiac magnetic resonance evaluation of the heart did not show any functional abnormalities. The patient was discharged on post-operative day (POD) #39 in good clinical conditions.
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Trasplante de Corazón , Isquemia Tibia , Humanos , Masculino , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/métodos , Persona de Mediana Edad , Isquemia Tibia/efectos adversos , Isquemia Tibia/métodos , Italia , Donantes de Tejidos , Obtención de Tejidos y Órganos/métodos , Preservación de Órganos/métodosRESUMEN
The Banff Heart Concurrent Session, held as part of the 16th Banff Foundation for Allograft Pathology Conference at Banff, Alberta, Canada, on September 21, 2022, focused on 2 major topics: non-human leukocyte antigen (HLA) antibodies and mixed rejection. Each topic was addressed in a multidisciplinary fashion with clinical, immunological, and pathology perspectives and future developments and prospectives. Following the Banff organization model and principles, the collective aim of the speakers on each topic was to ⢠Determine current knowledge gaps in heart transplant pathology ⢠Identify limitations of current pathology classification systems ⢠Discuss next steps in addressing gaps and refining classification system.
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Trasplante de Corazón , Trasplante Homólogo , Informe de Investigación , Leucocitos , Canadá , Rechazo de Injerto/patologíaRESUMEN
Fontan-type surgery is the final step in the sequential palliative surgical treatment of infants born with a univentricular heart. The resulting long-term haemodynamic changes promote liver damage, leading to Fontan-associated liver disease (FALD), in virtually all patients with Fontan circulation. Owing to the lack of a uniform definition of FALD and the competitive risk of other complications developed by Fontan patients, the impact of FALD on the prognosis of these patients is currently debatable. However, based on the increasing number of adult Fontan patients and recent research interest, the European Association for The Study of the Liver and the European Reference Network on Rare Liver Diseases thought a position paper timely. The aims of the current paper are: (1) to provide a clear definition and description of FALD, including clinical, analytical, radiological, haemodynamic, and histological features; (2) to facilitate guidance for staging the liver disease; and (3) to provide evidence- and experience-based recommendations for the management of different clinical scenarios.
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Diagnóstico por Imagen de Elasticidad , Procedimiento de Fontan , Hepatopatías , Adulto , Lactante , Humanos , Procedimiento de Fontan/efectos adversos , Hepatopatías/diagnóstico , Hepatopatías/etiología , Hepatopatías/cirugía , Pronóstico , Diagnóstico por Imagen de Elasticidad/métodosRESUMEN
Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, typically involving the extra-cranial branches of the carotid arteries and the thoracic aorta. Despite advances in noninvasive imaging, temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. To address this lack of uniformity, the Society for Cardiovascular Pathology formed a committee tasked with establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature. This consensus statement includes a discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery.
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The molecular refinement of the diagnosis of heart allograft rejection based on whole-transcriptome analyses faces several hurdles that greatly limit its widespread clinical application. The targeted Banff Human Organ Transplant gene panel (B-HOT, including 770 genes of interest) has been developed to facilitate reproducible and cost-effective gene expression analysis of solid organ allografts. We aimed to determine in silico the ability of this targeted panel to capture the antibody-mediated rejection (AMR) molecular profile using whole-transcriptome data from 137 heart allograft biopsies (71 biopsies reflecting the entire landscape of histologic AMR, 66 non-AMR control biopsies including cellular rejection and non-rejection cases). Differential gene expression, pathway and network analyses demonstrated that the B-HOT panel captured biologically and clinically relevant genes (IFNG-inducible, NK-cells, injury, monocytes-macrophage, B-cell-related genes), pathways (interleukin and interferon signaling, neutrophil degranulation, immunoregulatory interactions, endothelial activation) and networks reflecting the pathophysiological mechanisms underlying the AMR process previously identified in whole-transcriptome analysis. Our findings support the potential clinical use of the B-HOT-gene panel as a reliable proxy to whole-transcriptome analysis for the gene expression profiling of cardiac allograft rejection.
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Anticuerpos , Trasplante de Órganos , Humanos , Consenso , Biopsia , AloinjertosRESUMEN
Severe mucormycosis is a fatal disease rarely complicating chronic lymphoproliferative disorders. We present a fulminant and fatal case of a 74-year-old Caucasian woman suffering from CLL treated with second-generation BTK inhibitor zanubrutinib. After a first septic episode a month prior, originating from the lung with later systemic involvement by an unidentified agent and treated with large-spectrum antibiotics and fluconazonle, a slow-onset enlarging tender warm and erythematous nodular swollen cutaneous lesion appeared in her lower limbs and spread subsequently to her upper limbs, progressing towards central ulceration with a necrotic core. Suspecting a mycotic dissemination from an unknown agent, a skin punch biopsy was performed, and intraconazole was started. Due to spread of the skin lesions, the patient was hospitalized and intravenous liposomal ampthotericin B was started. Histopathology showed an atypical sporangium-rich mycotic angioinvasion of the small vessels. Only the increase of BDG and GM could corroborate the hypothesis of mycotic infection. However, long-term CLL, immunosuppressive therapies, neutropenia, and prior use of azoles and other antimycotic agents were risk factors for mucormycosis; BTK inhibitor could also be added as another novel risk factor. Despite all therapeutic efforts, the patient died. Post-mortem molecular exams confirmed the diagnosis of disseminated mucormycosis.
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Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.
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Cardiomiopatías , Cardiopatías , Insuficiencia Cardíaca , Sirtuina 3 , Humanos , Ratones , Animales , Sirtuina 3/genética , Regulación hacia Abajo , Ratones Endogámicos C57BL , Cardiomiopatías/inducido químicamente , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Miocitos Cardíacos/metabolismo , Doxorrubicina/farmacología , Cardiopatías/metabolismo , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , ApoptosisRESUMEN
BACKGROUND: The carotid stent design may influence the risk of embolization during carotid artery stenting. The aim of the study was to assess this risk by comparing the quantity of embolized material captured by filters during carotid artery stenting, using different stent designs. METHODS: We conducted a single-center retrospective study of patients undergoing carotid artery stenting for asymptomatic carotid stenosis >70% (2010-2022) in a tertiary academic hospital (Padua University Hospital, Italy). Carotid stents were classified according to their design as open-cell (OCS), closed-cell (CCS), or micromesh stents (MMS). A distal filter protection was used in all patients, and the amount of captured embolized particles was semiautomatically analyzed using a dedicated software (Image-Pro Plus, Media Cybernetics). Primary end point was embolic filter debris (EFD) load, defined as the ratio of the filter area covered by particulate material to the total filter area. Secondary end points were 30 days major stroke and death. RESULTS: Four-hundred-eighty-one carotid artery stentings were included; 171 (35%) using an OCS, 68 (14%) a CCS, and 242 (50%) a MMS. Thirty-days mortality was 0.2% (n=1) and major stroke rate was 0.2% (P=0.987). Filters of patients receiving MMS were more likely to be free from embolized material (OCS, 30%; CCS, 13%; MMS, 41%; P<0.001) and had a lower EFD load (OCS, 9.1±14.5%; CCS, 7.9±14.0%; MMS, 5.0±9.1%; P<0.001) compared with other stent designs. After stratification by plaque characteristics, MMS had a lower EFD load in cases of hypoechogenic plaque (OCS, 13.4±9.9%; CCS, 10.9±8.7%; MMS, 6.5±13.1%; P<0.001), plaque length>15 mm (OC, 10.2±15.3; CC, 8.6±12.4; MM, 8.2±13.6; P<0.001), and preoperative ipsilateral asymptomatic ischemic cerebral lesion (OCS, 12.9±16.8%; CCS, 8.7±19.5%; MMS, 5.4±9.7%; P<0.001). After multivariate linear regression, use of MMS was associated with lower EFD load (P=0.038). CONCLUSIONS: The use of MMS seems to be associated with a lower embolization rate and EFD load, especially in hypoechogenic and long plaques and in patients with a preoperative evidence of asymptomatic ischemic cerebral lesion.
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Estenosis Carotídea , Dispositivos de Protección Embólica , Embolia , Placa Aterosclerótica , Accidente Cerebrovascular , Humanos , Estenosis Carotídea/cirugía , Estenosis Carotídea/complicaciones , Estudios Retrospectivos , Resultado del Tratamiento , Stents/efectos adversos , Embolia/complicaciones , Accidente Cerebrovascular/complicaciones , Placa Aterosclerótica/complicaciones , Arterias Carótidas/cirugía , Arterias Carótidas/patologíaRESUMEN
BACKGROUND: Parietal epithelial cells are a heterogeneous population of cells located on Bowman's capsule. These cells are known to internalize albumin with a still undetermined mechanism, although albumin has been shown to induce phenotypic changes in parietal epithelial cells. Proximal tubular cells are the main actors in albumin handling via the macromolecular complex composed by ClC-5, megalin, and cubilin. This study investigated the role of ClC-5, megalin, and cubilin in the parietal epithelial cells of kidney biopsies from proteinuric lupus nephritis patients and control subjects and identified phenotypical changes occurring in the pathological milieu. METHODS: Immunohistochemistry and immunofluorescence analyses for ClC-5, megalin, cubilin, ANXA3, podocalyxin, CD24, CD44, HSA, and LTA marker were performed on 23 kidney biopsies from patients with Lupus Nephritis and 9 control biopsies (obtained from nephrectomies for renal cancer). RESULTS: Two sub-populations of hypertrophic parietal epithelial cells ANXA3+/Podocalyxin-/CD44-, both expressing ClC-5, megalin, and cubilin and located at the tubular pole, were identified and characterized: the first one, CD24+/HSA-/LTA- had characteristics of human adult parietal epithelial multipotent progenitors, the second one, CD24-/LTA+/HSA+ committed to become phenotypically proximal tubular cells. The number of glomeruli presenting hypertrophic parietal epithelial cells positive for ClC-5, megalin, and cubilin were significantly higher in lupus nephritis patients than in controls. CONCLUSIONS: Our results may provide further insight into the role of hypertrophic parietal epithelial cells located at the tubular pole and their possible involvement in protein endocytosis in lupus nephritis patients. These data also suggest that the presence of hypertrophic parietal epithelial cells in Bowman's capsule represents a potential resource for responding to protein overload observed in other glomerulonephritis.
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Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad , Nefritis Lúpica , Humanos , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Túbulos Renales Proximales , Proteinuria/etiología , Albúminas/metabolismo , Células Epiteliales/metabolismoRESUMEN
Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease at risk of sudden cardiac death and heart failure, even requiring heart transplantation. A "muscular mitral-aortic discontinuity" has been reported during surgery in the obstructive form. We aimed to validate these findings through pathological analysis of HCM heart specimens from the cardiovascular pathology tissue registry. Hearts with septal asymmetric HCM from sudden cardiac death, other causes of death, or heart transplantation were included. Sex-matched and age-matched patients without HCM served as controls. Gross and histologic analysis of the mitral valve (MV) apparatus and the mitral-aortic continuity were performed. Thirty HCM hearts (median age, 29.5 years; 15 men) and 30 controls (median age, 30.5 years; 15 men) were studied. In HCM hearts, a septal bulging was present in 80%, an endocardial fibrous plaque in 63%, a thickening of the anterior MV leaflet in 56.7%, and an anomalous insertion of papillary muscle in 10%. All cases but 1 (97%) revealed a myocardial layer overlapping the mitral-aortic fibrous continuity on the posterior side, corresponding to the left atrial myocardium. A negative correlation between the length of this myocardial layer and the age and the anterior MV leaflet length was found. The length did not differ between HCM and controls. Pathologic study of obstructive HCM hearts does not confirm the existence of a "muscular mitral-aortic discontinuity". An extension of left atrial myocardium, overlapping posteriorly the intervalvular fibrosa, is rather visible, and its length decreases with age, possibly as a consequence of left atrial remodeling. Our study highlights the fundamental role of thorough gross examination and the value of organ retention for further analysis in order to validate new surgical and imaging findings.
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Fibrilación Atrial , Cardiomiopatía Hipertrófica , Masculino , Humanos , Adulto , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/patología , Miocardio/patología , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/patología , Fibrosis , Muerte Súbita Cardíaca/patologíaRESUMEN
Background: Antibody-mediated rejection (AMR) is a serious complication affecting the survival of patients receiving transplantation. Human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are common viral infections that occur after transplantation, frequently emerging as viral reactivation in donor grafts or transplant recipients. The present study aimed to investigate the association between CMV and EBV infections and early-onset AMR. Materials and methods: This study was conducted at the Heart Transplantation Center of Padova General Hospital and included a cohort of 47 heart transplant recipients (HTxs), including 24 HTxs diagnosed with AMR and 23 control HTxs with no episodes of AMR. Only early cases of CMV and/or EBV infections (1-90 days after transplantation) were considered. Fisher's exact test and logistic regression analysis were used to statistically analyze the correlation and association between AMR and CMV or EBV infection. Results: We observed a positive statistical association between CMV and EBV infections (two-sided Fisher's exact test, p = 0.0136) and between EBV infection and AMR (two-sided Fisher's exact test, p = 0.0034). Logistic regression analysis revealed a direct statistical association between CMV and EBV infections and AMR risk (p = 0.037 and 0.006 and odds ratio = 1.72 and 2.19, respectively). AMR occurrence was associated with increased viral loads of both CMV and EBV early after transplantation. Discussion: These findings suggest the role of CMV and EBV infections as relevant risk factors for AMR in HTxs for the first time.
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Infecciones por Citomegalovirus , Infecciones por Virus de Epstein-Barr , Trasplante de Corazón , Humanos , Citomegalovirus , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Infecciones por Citomegalovirus/complicaciones , Factores de Riesgo , Anticuerpos , Trasplante de Corazón/efectos adversosRESUMEN
Coronary collateral arteries (CCAs) are anastomotic channels between vessels; although beneficial in atherosclerosis, their role in heart transplantation (HT) recipients is underinvestigated. CCAs initially develop as microcirculation and cardiac allograft vasculopathy (CAV), promoting immune-dependent proliferative angiogenic response, and play a role in their development. In our hypothesis, ischemia induced by coronary microvascular dysfunction (CMD) triggers the development of CCAs, which are, in turn, less functional as affected by CAV themselves. Methods: One hundred twenty-one patients receiving HT at our institution were retrospectively evaluated and were included if transthoracic echocardiography with coronary flow velocity reserve (CFVR) assessment and coronary angiography were performed. CMD was defined as CFVR of ≤2.5. Patients with CAV were enrolled, and their angiograms were reviewed to evaluate the presence of CCAs. Cardiovascular mortality was assessed as the main clinical outcome. Results: Forty patients were found to have CCAs. Patients with CCAs have lower CFVR than those without CCAs (2.22 ± 0.72 versus 2.69 ± 0.92;P = 0.003), reflecting in different rates of CMD in the 2 groups (72.5% versus 37%; P < 0.001). CMD is associated with higher CAV grades (P < 0.001), which are also associated with CCAs (P < 0.001). Patients with poorly developed CCAs have lower CFVR (P < 0.001). At multivariable analysis, CMD (P = 0.008) and higher CAV grades (P = 0.005) are independent predictors of CCAs. During the median follow-up time of 10.2 (6.6-13.3) y, patients with CCAs have been found to have higher mortality than those without CCAs (57.5% versus 32.1%; P = 0.007). CCAs are associated with a lower probability of survival also in patients with CMD (P < 0.001) and are independent predictors of mortality (P < 0.001). Conclusions: Our results demonstrate an interplay between CAV, CMD, and CCAs. We confirm that CAV is associated with CMD, and we show, for the first time, that CMD is associated with CCAs. CCAs are pathophysiologically associated with more severe graft vasculopathy and independently predict mortality after HT.