Assessment of sex- and age-dependency of risk factors for intimal hyperplasia in heart transplant patients using the high resolution of optical coherence tomography☆
Introduction
Cardiac allograft vasculopathy (CAV), defined as intimal hyperplasia (CAVIH) in intracoronary imaging and/or lesions in angiography (CAVangio), remains one of the leading causes of mortality and graft failure in pediatric and adult patients after heart transplantation (HTx) [1,2]. Yet, there are important gaps of knowledge regarding individual prevention options. A better understanding of HTx subpopulations that are particularly at risk for CAV development and progress might help optimize primary and secondary prevention strategies. In particular, whether the predictive value of current risk factors depends on age or sex of HTx patients remains unknown. Current recommendations regarding medical CAV prevention are largely based on data obtained in adults and few risk factors have been validated in pediatric HTx patients [3]. The impact of conventional cardiovascular risk factors is of special clinical interest, as they often occur with a considerably higher prevalence in pediatric and adult HTx patients than in the non-transplanted population, mainly due to immunosuppression [4,5]. Based on differences regarding evolving atherosclerotic plaques, age-dependent effects of cardiovascular risk factors in adult and pediatric HTx patients have been suggested [6]. While the interaction of gender and cardiovascular risk factors in coronary disease is known in non-transplanted patients, it has not been evaluated in HTx patients [7].
In addition, previous risk factor association with CAVIH has mainly been performed using intravascular ultrasound (IVUS) [8,9]. Notably, due to the limitation of IVUS resolution, the differentiation of intima and media is challenging in IVUS [10,11]. Therefore, IVUS studies assessing risk factors for CAVIH have mainly used values of combined intima - media thickness and not intima thickness alone [12,13]. Optical coherence tomography (OCT) has a 10-fold higher spatial resolution and is therefore more accurate in distinguishing intima and media, and detecting CAVIH [[14], [15], [16]]. The correlation of OCT findings with histopathology is high, thereby offering further insights into the analysis of CAVIH [16]. In pediatric HTx patients, studies correlating risk factors with CAVIH using OCT are scarce.
The primary objective of our study was to assess the age- and sex-dependency of established risk factors regarding the prevalence of pathological CAVIH in OCT in pediatric and adult HTx patients.
Section snippets
Study population
We analyzed routinely performed OCT examinations of pediatric and adult HTx patients between December 2013 and October 2019 at our center. The study was approved by the local institutional review board and performed in accordance with the ethical standards and the Declaration of Helsinki and its later amendments. All patients were informed about potential risks of the examination prior to the angiography and OCT examination, and written informed consent was obtained. Analyses were performed
Overall population
We included 102 patients were included into this analysis. 36 patients (35.3%) were aged <18 years. Of all patients, 70 patients (68.6%) were male. The post-transplant interval was 9.6 [IQR 5.0–13.1] years. In the overall population, 52 patients (51.0%) presented with CAVIH in OCT. We analyzed a mean of 10 frames/patient. Fig. 1 shows an example of CAVIH in our cohort.
Population characteristics according to age category and presence of CAVIH
Characteristics according to age and CAVIH category are shown in Table 1. In the pediatric cohort, 9 patients (25%) presented
Discussion
To the best of our knowledge, this is the first observational study assessing the age- and sex-dependent impact of risk factors for CAVIH on the basis of the high resolution of intracoronary OCT in adult and pediatric HTx patients. The main findings of our study can be summarized as follows: there were age- and sex-dependent differences as (1) dyslipidemia was associated with CAVIH in all subgroups, but had a particularly strong association in women and adult patients, and (2) CAVIH was
Conclusion
We could demonstrate age- and sex-dependent differences in risk factors, as dyslipidemia was associated with higher likelihood of CAVIH in all patients, but the association was stronger in female and adult patients than in male and pediatric patients. Total cholesterol was associated with CAVIH only in female and pediatric patients. Diabetes increased the risk for CAVIH only in female patients. As opposed, arterial hypertension and donor age increased the risk for CAVIH independently of age and
Limitations
As this is a cross-sectional study, our results correlate risk factors with CAV prevalence at the time point of OCT, but not with CAV progression or outcome. Albeit the absolute number of patients in our study is limited, our cohort is comparable or even larger than other OCT studies with HTx patients. While studies indicate that OCT could add important additional information regarding CAV detection and progress, there are no prospective evaluating a potential benefit of OCT over IVUS in
Funding sources
Dr. Mehilli reports funding of German Centre for Cardiovascular Research (DZHK) for material costs of optical coherence tomography and image analysis.
Disclosures
Dr. S. Ulrich used retrospectively some OCT data that had also been previously used in a study supported by Novartis Pharma GmbH. Novartis Pharma GmbH was not involved in the development, realization and data analysis of this study. Dr. Ulrich reports grants from Astellas Pharma GmbH, outside the submitted work. J. Neubarth-Mayer reports grants from German Centre for Cardiovascular Research (DZHK), during the conduct of the study. Dr. Martin Orban reports personal fees from AstraZeneca,
Author statement
Madeleine Orban, Sarah Ulrich, Dominic Dischl, Janina Neubarth-Mayer, Anna Strüven participated in the data collection. Madeleine Orban, Sarah Ulrich and Steffen Massberg participated in the writing of the article, analytic tools and research design. Markus Dietl participated in the data curation and analysis. Patrick von Samson-Himmelstjerna, Marcus Fischer, Anja Tengler, Andre Jakob, Tobias Petzold, Konstantinos Rizas, Martin Orban, Daniel Braun, Jörg Hausleiter, Nikolaus A. Haas, Christian
References (49)
- et al.
The registry of the International Society for Heart and Lung Transplantation: nineteenth pediatric heart transplantation Report-2016; focus theme: primary diagnostic indications for transplant
J. Heart Lung Transplant.
(2016) - et al.
The registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation Report-2017; focus theme: allograft ischemic time
J. Heart Lung Transplant.
(2017) - et al.
Management of dyslipidemia in adult solid organ transplant recipients
J Clin Lipidol.
(2019) - et al.
Hyperlipidemia in children after heart transplantation
J. Heart Lung Transplant.
(2006) - et al.
Optical coherence tomography for characterization of cardiac allograft vasculopathy in late survivors of pediatric heart transplantation
J. Heart Lung Transplant.
(2016) - et al.
Correlation of donor characteristics with transplant coronary artery disease as assessed by intracoronary ultrasound and coronary angiography
Am. J. Cardiol.
(1995) - et al.
American College of Cardiology Clinical Expert Consensus Document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American College of Cardiology Task Force on clinical expert consensus documents
J. Am. Coll. Cardiol.
(2001) - et al.
Comparative study of pediatric coronary allograft vasculopathy between single centers in North America and United Kingdom
Transplant. Proc.
(2018) - et al.
Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study)
J. Heart Lung Transplant.
(2013) - et al.
Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the international working Group for Intravascular Optical Coherence Tomography Standardization and Validation
J. Am. Coll. Cardiol.
(2012)
Safety of optical coherence tomography in pediatric heart transplant patients
Int. J. Cardiol.
OCT assessment of allograft vasculopathy in heart transplant recipients
JACC Cardiovasc. Imaging
Comparison of the endothelial surface and subjacent elastic lamina of anterior descending coronary arteries at the location of atheromatous lesions with internal thoracic arteries of the same subjects: a scanning electron microscopic study
Pathology.
Systemic inflammation and metabolic syndrome in cardiac allograft vasculopathy
J. Heart Lung Transplant.
Diverse morphologic manifestations of cardiac allograft vasculopathy: a pathologic study of 64 allograft hearts
J. Heart Lung Transplant.
Layered fibrotic plaques are the predominant component in cardiac allograft vasculopathy: systematic findings and risk stratification by OCT
JACC Cardiovasc. Imaging
Cardiac allograft vasculopathy: differences of absolute and relative intimal hyperplasia in children versus adults in optical coherence tomography
Int. J. Cardiol.
Survival, graft atherosclerosis, and rejection incidence in heart transplant recipients treated with statins: 5-year follow-up
J. Heart Lung Transplant.
The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients
J. Heart Lung Transplant.
Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study
J. Am. Coll. Cardiol.
Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation
J. Heart Lung Transplant.
Gender-specific care of the patient with diabetes: review and recommendations
Gend Med.
An intravascular ultrasound study of the influence of angiotensin-converting enzyme inhibitors and calcium entry blockers on the development of cardiac allograft vasculopathy
Am. J. Cardiol.
Impact of donor benign intimal thickening on cardiac allograft vasculopathy
J. Heart Lung Transplant.
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This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation