Successful Management of a Pregnant Patient with Danon Cardiomyopathy

Abstract

A 25-year-old woman with left ventricular (LV) dysfunction became pregnant during the diagnostic period. Decompensated heart failure with frequent ventricular arrhythmias necessitated hospitalization in the 21st week of pregnancy. Under careful monitoring, diuretics and sotalol were added to her ongoing treatment of carvedilol and spironolactone due to the risk of hemodynamic collapse. An emergency cesarean section was performed in the 32nd week after the detection of rapid nonsustained ventricular tachycardia. Subsequent genetic testing revealed that the LV dysfunction was associated with Danon cardiomyopathy. This case highlights the importance of careful pregnancy management with LV dysfunction along with early genetic testing.

Introduction

There are several case reports of pregnancy in patients with heart failure resulting in successful delivery (1). However, in pregnancies involving left ventricular (LV) dysfunction there is an increased risk of poor maternal and fetal outcomes (1,2). Especially for inherited diseases causing progressive cardiac decompensation, multidisciplinary management is needed.

Danon's disease (DD) is an inherited X-linked dominant metabolic disorder of unknown prevalence in the general population (3). DD is also known as glycogen storage disease type IIb based on mutations identified in the lysosome-associated membrane protein type 2 (LAMP2) gene (4). LAMP2 deficiencies impair the fusion of lysosomes to autophagosomes in the autophagic process, leading to mitochondrial dysfunction, energy deficiency, and oxidative stress (4). The early recognition of DD is difficult in women since a number of extracardiac features, including skeletal myopathy, mental retardation, hepatic disorders, and retinal disease, only manifest in some patients (4). In men, Danon cardiomyopathy (DC) typically presents as hypertrophic cardiomyopathy (HCM) before progressing to dilated cardiomyopathy (DCM) (5). In female patients, however, HCM and DCM have a similar prevalence (5). Cardiac symptoms begin to appear at approximately 30 years of age, which is approximately 15 years later than in men. Afflicted women have a mean survival age of 45 years due to X-linked inheritance (4). Implantable cardioverter defibrillator (ICD) placement can help extend the lives of DC patients (4), and heart transplantation is performed, especially in male patients of approximately 18-19 years of age (6).

An increasing number of DD cases are being discovered with the availability of genetic testing. As a result, there may also be a greater need for physicians skilled in managing DC in pregnant women. To the best of our knowledge, there is currently no literature on management strategies for pregnancy in DC. The present report described the successful management of pregnancy in a patient with DC accompanied by frequent ventricular tachycardia.

Case Report

A 25-year-old woman was referred to our hospital for further examination of abnormal electrocardiography (ECG) findings. Although some ECG and echocardiography abnormalities had been noted when she was a high school student, no assessments had been performed since. Her chief complaints were palpitations and dyspnea during exercise. Her medical history was unremarkable apart from an appendectomy. Familial history revealed unspecified arrhythmia in her paternal grandfather, with no record of sudden cardiac death (Fig. 1).

Figure 1.

No other family members of the patient have undergone genetic testing and developed clinical symptoms based on Danon disease based on their pedigree.

A chest X-ray of the patient showed no cardiomegaly, pulmonary edema, or congestion. ECG revealed sinus rhythm, poor R progression, negative T waves in II, III, aVF, and V4-6, and frequent premature ventricular contractions (PVCs) (Fig. 2). Echocardiography revealed enlargement of the LV cavity [LV diameter diastolic/systolic (LVDd/Ds): 53/41 mm], reduced systolic function [LV ejection fraction (LVEF): 48%], and thinning of the left posterior ventricular wall (7 mm) and interventricular septum (8 mm). A blood examination detected slightly increased brain natriuretic peptide (BNP) (113 pg/mL). Creatine kinase was in the normal range throughout the course of the disease. Twenty-four-hour Holter ECG monitoring confirmed her frequent PVCs (4,519/day) and a maximum rate of nonsustained ventricular tachycardia (NSVT) of 120 bpm (15/day) (Fig. 2). Cardiovascular magnetic resonance imaging showed late gadolinium enhancement in the endocardium of the entire left ventricle (Fig. 3). Coronary angiography demonstrated no stenosis, and a myocardial biopsy sample revealed cardiomyocytes with swollen nuclei and vacuolar degeneration as nonspecific findings.

Figure 2.

ECG disclosed sinus rhythm with multifocal frequent PVCs, poor R progression, and negative T waves in II, III, aVF, and V4-6. Twenty-four-hour Holter ECG monitoring demonstrated her NSVT.

Figure 3.

Cardiovascular magnetic resonance imaging (short-axis view) showed late gadolinium enhancement in the endocardium of the entire left ventricle.

The introduction of treatment for LV dysfunction in parallel with further genetic testing has been recommended for patients desiring pregnancy (7). However, neither the woman nor her family expressed a desire for pregnancy or genetic testing. Enalapril and carvedilol were commenced. A few months later, she unexpectedly became pregnant, at which time enalapril was immediately switched to spironolactone.

During the 21st week of pregnancy, palpitations, fatigue, and dyspnea with elevated BNP (183 pg/mL), LVEF 40% (Fig. 4), increased PVCs (6,831/day), and NSVT (154/day) were observed. She was admitted to our hospital with a diagnosis of decompensated heart failure (New York Heart Association functional classification III) resulting from the progression of LV dysfunction with frequent NSVT due to volume overload.

Figure 4.

Echocardiography on admission revealed reduced systolic function (LVEF: 40%) as compared with her first visit. During pregnancy, the left ventricular cavity was enlarged and LVEF decreased right before delivery.

Low-dose furosemide was included in her ongoing therapy to limit volume overload progression. Low-dose sotalol was also added, which we adjusted with frequent monitoring of the cardiac function to prevent the progression to lethal ventricular arrhythmias not adequately suppressed by carvedilol alone. Her BNP level decreased and was maintained at approximately 100-150 pg/mL. Carvedilol and furosemide were gradually increased while carefully monitoring her symptoms, BNP level, ventricular arrhythmia frequency, and infant growth.

In the 32nd week of pregnancy, an emergency cesarean section was performed with percutaneous cardiopulmonary support on stand-by due to the appearance of a marked increase in the NSVT rate (180/min) and dizziness. This procedure was selected over vaginal delivery to avoid afterload mismatch from elevated blood pressure and lethal ventricular arrhythmias due to increased sympathetic nerve activity. The surgery was successful, and she gave birth to a healthy boy weighing 1,606 g, with 1- and 5-minute APGAR scores of 6 and 7, respectively.

Following delivery, sacubitril/valsartan was commenced, and carvedilol was increased to 6.25 mg. A low dose of sotalol was maintained until the suppression of persistent PVCs and NSVT was sufficient to prevent sudden cardiac death (Fig. 5). Although the baby was initially managed in the neonatal intensive care unit with intubation, both the mother and child were safely discharged without major sequelae.

Figure 5.

Brain natriuretic peptide, body weight and the frequency of PVCs with appropriate drug adjustments during pregnancy.

Subsequently, we again offered her genetic testing to investigate possible secondary genetic cardiomyopathy. After receiving her informed consent, a nonsense variant LAMP2 gene mutation (c.877C>T:p. Arg293*) was identified, leading to a final diagnosis of DC. The parents did not request genetic testing of the child.

An ICD was implanted at 1 year after discharge since her DC was associated with a progressive decline in her cardiac function and there was considered to be a high probability of sudden cardiac death. Moreover, atrial pacing was deemed necessary to ensure an adequate heart rate with increasing doses of carvedilol. Heart transplantation is being considered for the future.

Discussion

Pregnancy with heart failure

Preexisting cardiac disease may lead to heart failure as a result of pregnancy-induced hypervolemia. The primary cause of heart failure during the peripartum period originates from the physiological demands of labor and birth placing an excessive burden on the compromised cardiac function. Ng et al. reported that heart failure increased the risk of death 7.7-fold (8). Maternal heart failure may also cause fetal growth restrictions, low birth weight, and death (8,9).

Although vaginal delivery is preferable in patients with stable DCM, cesarean section delivery is recommended for the mother's safety when heart failure progresses or in the presence of hemodynamic instability (2). An early cesarean section can reduce the maternal cardiovascular burden but may also lead to low birth weight. Careful observation of the fetus and mother is therefore essential when determining the best mode of delivery.

In the reported case, both volume overload and ventricular arrhythmias were well managed by diuretics and β-blockers. An emergency cesarean section was performed in the 32nd week of pregnancy due to frequent rapid NSVT, which contributed to an elevated risk of hemodynamic collapse. Important factors in this case included the careful monitoring of the maternal hemodynamics and close cooperation among healthcare providers during the patient's daily care. As a result, no serious complications occurred, and the baby was born in good health.

Usefulness of genetic testing in LV dysfunction

Genetic testing is becoming an indispensable tool for understanding the diagnosis, etiology, and prognosis of many diseases, including cardiomyopathy of unknown cause, which in turn may enable more timely and appropriate treatment recommendations (10). In a reported case, the patient was at high risk of sudden cardiac death due to progressive LV dysfunction and lethal arrhythmia caused by DC, which necessitated ICD implantation. Even if heart failure is optimally treated, eventual heart transplantation is often needed. Genetic testing can provide opportunities for making timely decisions before disease progression.

On the other hand, there are several issues in applying genetic testing to real clinical practice (11). A misunderstanding of genetics may lead to discrimination against patients and their families. Moreover, genetic testing is still not sufficiently recognized as a useful method in the general population, and it is difficult to obtain consent in many cases. Even when genetic testing is available, considerable time is needed to obtain results, creating a lag in the provision of optimal treatment. Finally, despite the high cost of testing, critical findings are not identified in many cases. However, with the development of specific treatments based on a patient's genetic background and the advancement of testing accuracy, the usefulness of this tool is expected to gain more traction in the general population.

Pregnancy with Danon cardiomyopathy

Although there are no existing reports on the characteristics of DC in terms of pregnancy and delivery, it is considered preferable to begin pregnancy as early as possible before the progression of cardiac dysfunction in patients who strongly desire to have children.

In addition, it should be made clear that DC is an inherited condition and that the child has at least a 50% chance of harboring the disease. Male offspring will suffer cardiomyopathy earlier in life and have a shorter lifespan, whereas female offspring can expect the onset to occur at a later age and to have a comparably longer life expectancy (4). Patients of both sexes may require heart transplantation. One important lesson from this case is that the genetic screening of women with LV dysfunction before pregnancy is crucial since they may be discovered to have a DC background. Such testing will help patients and their physicians make more informed choices when deciding to have children. Although this patient had no desire for genetic testing when it was diagnosed as idiopathic DCM, in retrospect, the results of cardiac biopsy indicated that vacuolar degeneration may be a finding that suggested DC (12).

Appropriate drugs and devices in the peripartum period

The practice of ICD implantation in pregnant women prior to delivery to prevent life-threatening ventricular arrhythmia is controversial. ICD placement during pregnancy and the small amounts of electrical shock transferred to the uterus may harm the fetus (13,14). ICDs should therefore be considered based on sudden cardiac death risk and patient benefit in each case, referring to the guidelines of ICD implantation under LV dysfunction.

Finally, angiotensin-coverting enzyme (ACE) inhibitors or sacubitril/valsartan, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid receptor antagonists (MRA) are the standard medications for heart failure but should not be given to pregnant women due to their teratogenicity; β-blockers, diuretics, and vasodilators may be suitable instead. Soon after delivery, the inhibition of the renin-angiotensin-aldosterone system should be resumed, and ICD implantation and heart transplantation should be considered to improve the long-term prognosis.

In conclusion, this case report demonstrated that pregnancy and delivery could be safely managed by suppressing fatal arrhythmias and controlling hemodynamics, even in cases of DC. Constant monitoring of arrhythmias, frequent evaluation of hemodynamics, and drug regimen adjustment according to the condition of the mother and fetus were all important. For the mother's safety, additional precautions should be taken before pregnancy to prevent the exacerbation of arrhythmias and heart failure, including genetic testing and possible ICD implantation. Pregnancy management in DC will become more prominent in the future as genetic screening becomes widespread, creating a need to establish treatment standards to protect the mother and child.

The authors state that they have no Conflict of Interest (COI).