Enzyme Replacement and Immunosuppression in Heart Transplant Recipients with Fabry Cardiomyopathy: A 7-Year Case Study

Introduction

Fabry disease (FD) is a rare genetic storage disorder leading to the abnormal accumulation of glycosphingolipids in numerous organs [1]. It results from mutations in the X-linked GLA gene, causing a deficiency or absence of alpha-galactosidase A (α-Gal A) [1]. The clinical presentation of FD can vary between patients. There are 2 main types of FD [2]. The early-onset type, also referred to as “classic”, involves many organs, while the late-onset type affects only 1 organ, usually the heart, kidneys, or central or peripheral nervous systems [3]. Thus, common symptoms of the disease include burning pain in the extremities, hearing loss, gastrointestinal manifestations, anhidrosis or hypohidrosis, angiokeratoma, renal and cardiac failure [4], and severe neurological complications such as ischemic stroke [5,6].

Usually, male patients are more likely to present cardiovascular symptoms of the disease at a younger age compared to females [7]. However, women can present with a wide range of symptoms, from single-organ involvement to an almost “classic” type of the disease [5,6]. Differences in severity and organ involvement between male and female patients are mainly caused by inactivation of the GLA wild allele on the X chromosome, as there is a correlation between the level of inactivation and disease severity [8–12].

Characteristic features of Fabry cardiomyopathy may be observed even in the most common of cardiologic diagnostic tests. For instance, while performing an ECG, we may observe a short P wave resulting in the shortening of the PQ interval, as well as QT and QRS prolongation, atrioventricular and bundle branch blocks, bradycardia, atrial fibrillation, and signs of left ventricular hypertrophy (LVH) [13]. Echocardiography may reveal features of LVH, various disorders in the posterior basal wall (hyperdensity, thinning, akinesia), abnormal contraction of segments affected by fibrosis, normal systolic function combined with diastolic dysfunction, and disorders and thickening of the aortic and mitral valves [14]. Features of FD in cardiac MRI are similar to those present in echocardiography. Additionally, late gadolinium enhancement of the mid-myocardial layer of fibrosis-affected segments and a decrease in T1 of non-affected segments may be visible [14,15].

The aim of this case study is to present the long medical history of a female patient with FD who underwent a heart transplant due to the progression of Fabry cardiomyopathy and thereafter had a favorable course of the disease on ERT and immunosuppressive therapy.

To the best of our knowledge, there are very few documented cases of heart transplantation in patients with FD worldwide, with only 1 presenting a woman (Table 1).

Case Report

The chest X-ray of a 38-year-old woman, conducted as part of a routine check due to shortness of breath, uncovered an enlarged cardiac silhouette. Further diagnostics included transthoracic echocardiography (TTE), which showed concentric left ventricular hypertrophy (LVH) with a maximum diastolic intraventricular septum thickness of 13 mm and posterior wall thickness of 12 mm. Electrocardiography (ECG) disclosed a normal sinuous rhythm at 72 bpm with features of left ventricular hypertrophy. A treadmill exercise test, 24-hour Holter monitoring (24hHM), and dobutamine stress echocardiography, performed due to chest pain at rest, did not reveal additional abnormalities. Eventually, hypertrophic cardiomyopathy was diagnosed and typical therapy with beta-blockers was initiated.

TTE performed during a routine cardiac evaluation after 6 years suggested a storage disorder as the underlying cause of LVH. ECG revealed bradycardia and deep inverted T waves in V4-V6 leads, and 24-hour Holter monitoring revealed episodes of nonsustained ventricular tachycardia. Therefore, diagnostics were extended with cardiac magnetic resonance imaging (cMRI). T1 mapping confirmed LVH and revealed subendocardial late gadolinium enhancement in inferolateral segments of LV (Figure 1). A high level of lyso-Gb3 (Figure 2) and positive genetic testing confirmed the diagnosis of FD. Heterozygous mis-sense mutations (c.138C>F [p.His46Gln], c.153G>T [p.Met51Ile], c.167G>T [p.Cys56Phe]) were identified.

The patient was the first one diagnosed with FD in her family. Further genetic screening revealed that her mother, brother, 2 sisters, son, and niece also had FD.

At the time of diagnosis, enzyme replacement therapy (ERT) was not available in Poland, so the patient received standard conservative treatment with beta-blockers and was scheduled for regular check-up visits. Despite the therapy, over the following 2 years the heart failure symptoms aggravated to the point of resting dyspnea, and the patient was placed on the waiting list for a cardiac transplant. Orthotopic heart transplantation (OHT) was performed in June 2016. During the early postoperative period, there were no signs of cardiac complications or transplant rejection. Nevertheless, there was a temporary, moderate deterioration in renal function (creatinine 78.0 μmol/L a year before OHT vs 146 μmol/L 3 months after OHT), most probably related to transient ischemia during the surgery and the high doses of immunosuppressive agents administered afterwards. Renal parameters normalized and remained within nearly normal ranges (from 92.5 μmol/L to 107.3 μmol/L 6 years after OHT). Additionally, an ultrasonography performed soon after OHT disclosed a thrombus in the right internal jugular vein, without any severe clinical implications or further consequences. Further recovery after OHT went uneventfully, and improvement in clinical symptoms and biochemical parameters (NT-proBNP, hsTnT, CK-MB mass) was observed (Figure 2). Until late 2019, when ERT became reimbursable in Poland, the patient was treated solely according to standard post-transplant care.

In early 2020, as the patient’s mutations were non-amenable to treatment with chaperone therapy, she was included in the ERT qualification process. A detailed medical examination focused on FD symptoms revealed acroparaesthesia, anhidrosis, and angiokeratomas. All of these symptoms had been present since childhood but were never previously associated with FD. A brain MRI, required for the ERT program, revealed multiple lesions in the white matter and pons, as well as post-ischemic cavities in the right lenticular nucleus, right internal capsule (15×15×6 mm), and the left side of the thalamus (12×13×4 mm). Similar abnormalities are often seen in patients with lysosomal storage disorders. However, prior to the OHT, no brain MRI or CT was performed.

Finally, she received approval for ERT with the standard agalsidase-beta dose of 1 mg/kg. The first administration of this drug took place in June 2020. This infusion lasted 3.5 hours, and no adverse effects were observed. Therefore, the duration of following infusions was shortened to 1 hour 45 minutes. Until now, the patient has received over 100 doses of ERT, and the therapy has been ongoing for over 50 months. No adverse effects of ERT have been noticed. Throughout ERT administration, regular clinical and laboratory assessments have been performed every 6 months. Additionally, the patient remains under the care of a heart transplant center. Deferred analysis of the endomyocardial biopsy performed 5 years after the heart transplant did not reveal any accumulation of glycosphingolipids (Figure 3). Regular echocardiographic check-ups showed no abnormalities, with a left ventricular ejection fraction of 66% and cardiac wall thickness within the normal range. Moreover, levels of high-sensitivity troponin and NT-proBNP have remained low since the OHT (Figure 2). Interestingly, since the beginning of ERT, a progressive reduction in lyso-Gb3 has been observed (Figure 2). Due to the limited availability of tests for anti-drug antibodies (ADA) against ERT, we have not evaluated the presence or levels of ADA. The course of therapy was complicated in June 2022 by CMV infection-related meningitis. Typical antiviral treatment with ganciclovir was successfully conducted. The immunosuppressive treatment was probably the underlying cause of this infection.

Despite ERT, the patient is currently treated with tacrolimus (1 mg twice a day), mycophenolate mofetil (500 mg twice a day), ramipril (2.5 mg), lacidipine (2 mg), atorvastatin (10 mg), acetylsalicylic acid (75 mg), and pantoprazole (40 mg). No interactions between ERT and the immunosuppressive drugs have been observed. The tacrolimus blood concentration remains stable.

Discussion

The presented case of this female patient is an example of late-onset FD with cardiac involvement. Despite treatment, the progression of Fabry cardiomyopathy in the patient was extremely unfavorable and quickly led to severe heart failure, which was managed with cardiac transplantation. The 6-year post-transplant follow-up, including ERT administration starting in 2022, has been successful.

Heart failure is diagnosed in about 20% of untreated females with FD and in about 15% of females with late-onset FD [21]. The literature contains only a few cases of heart transplantations in patients with FD, mostly reported in men. In all described cases, no signs of FD-related heart involvement were observed in the years following OHT, and most patients received ERT (Table 1). These reports are consistent with our observations. Our patient’s biochemical markers levels, cardiac functions assessments, and imaging tests did not reveal any abnormalities, which corresponded well with the patient’s good clinical status. However, heart involvement in FD typically takes years to develop, and the follow-up periods in the aforementioned case reports might have been too short. It is also important to consider that the heart donor was likely free of FD, so the graft’s cardiomyocytes may produce enough alpha-galactosidase to cause a protective effect, but this hypothesis requires further research.

The clinical course of patients with FD after heart transplantation may be influenced by 2 therapeutic components: ERT and post-transplant immunosuppression. ERT usually decelerates the progression of FD but rarely leads to a complete cessation of the disease [22]. However, post-transplant patients who received ERT presented noticeably better graft function compared to those who did not receive ERT [23]. Interestingly, a report described a patient with FD who received only immunosuppressive drugs (without ERT), and 4 years after the transplant, there was no evidence of cardiac involvement [20]. A similar situation was observed in our patient, who received immunosuppressive treatment without ERT for more than 3 years, and combined ERT and immunosuppressive therapy for more than 4 years. During this period, her cardiac biomarkers remained low. Moreover, a similar phenomenon was observed in patients who underwent renal transplants. In this population, individuals who received ERT and anti-rejection drugs rarely presented pathological renal changes related to FD [17,24–27]. It is important to note that the follow-up periods in the aforementioned reports might be insufficient. Nonetheless, observing such a phenomenon appears to be a promising area for further investigation regarding the role of immunosuppressive therapy in FD progression.

One study suggests that cardiac involvement in FD can be caused by autoimmune cardiomyositis [28]. The authors propose that the production of anti-heart and anti-myosin antibodies is triggered by the necrosis of lyso-Gb3-loaded myocytes. However, this study is limited by its small sample size, and further research is needed on this topic. Other studies suggest that lyso-Gb3 accumulation by itself, as well as the oxidative stress it causes, can trigger an inflammatory response [29]. These mechanisms could potentially be targets for immunosuppressive agents.

The reduction of ADA levels, the presence of which can diminish the effectiveness of ERT, may also be an important explanation for this observation [30]. Reports describe successful reduction of ADA levels in patients undergoing immunosuppressive therapy and in a mouse model of FD [31,32]. Although there are insufficient data to confirm that hypothesis, the administration of anti-rejection drugs administration may contribute to a reduction in ADA levels, leading to a better response to ERT.

This case report has significant limitations, primarily due to limited access to medical documentation and laboratory tests from the period when the patient was not under our team’s care. The cMRI images obtained before OHT were saved in limited sequences and low quality; therefore, we primarily relied on the radiological description. The histopathological samples were incomplete and of poor quality, which limited our analysis and the material available for illustration. Since anti-drug antibody testing is not available in our center’s laboratory, we were unable to monitor its levels during follow-up.

Conclusions

Severe heart failure not responding to medical therapy in patients with FD can be managed effectively with cardiac transplantation. Although the risk of disease recurrence in the transplanted organ appears to be relatively low, this observation requires further investigation with extended follow-up and a larger study sample. The anti-inflammatory effects of post-transplant immunosuppressive therapy could potentially contribute to this outcome, but additional research is needed.