Assessment of sex- and age-dependency of risk factors for intimal hyperplasia in heart transplant patients using the high resolution of optical coherence tomography

https://doi.org/10.1016/j.ijcard.2022.04.042Get rights and content

Highlights

  • Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation.

  • Intimal hyperplasia in intracoronary imaging (CAVIH) is a main determinant of CAV.

  • Whether the predictive value of risk factors is age- or sex-dependent is unknown.

  • Diabetes and dyslipidemia had a different impact on CAVIH depending on age and sex.

  • Total cholesterol was relevant regarding CAVIH only in women and children.

Abstract

Background

Intimal hyperplasia in cardiac allograft vasculopathy (CAVIH) is limiting survival in pediatric and adult patients after heart transplantation (HTx). Analysis of risk factors for CAVIH using the high resolution of intracoronary optical coherence tomography (OCT) is scarce, particularly in children, and recommendations for CAV prevention are largely based on data obtained in adults. Whether the predictive value of risk factors is age- or sex-dependent is unknown.

Methods and results

We used OCT to test the age- and sex-dependency of established risk factors regarding pathological CAVIH in a cohort of 102 pediatric and adult HTx patients (35% <18 years, 69% male). Modifiable parameters such as lipid values, and the diagnoses of dyslipidemia and diabetes showed age- and sex-dependent differences. Regarding CAVIH, receiver-operating characteristic analysis showed that LDL-c was relevant only in female patients (area under the curve [AUC] 0.79, p = 0.007), and total cholesterol in female (AUC 0.81; p = 0.004) and pediatric patients (AUC 0.73, p < 0.05). The association of dyslipidemia with CAVIH was stronger in adult (odds ratio [OR] 6.33) than in pediatric patients (OR 5.00) and in women (OR 6.00) than in men (OR 4.57). Diabetes was associated with CAVIH only in women (OR 11.25).

Conclusion

In our cohort, modifiable risk factors, particularly total cholesterol and dyslipidemia, had a different impact depending on age and sex. Targeting risk factors in selected patients might improve individual CAVIH prevention.

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

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