Bệnh cơ tim do Hydroxychloroquine—Một loạt ca bệnh và Tổng quan tài liệu

Abstract

Cardiomyopathy is a rare but serious adverse effect of long-term hydroxychloroquine therapy, manifesting as conduction abnormalities and heart failure. Its incidence is not well established. We present the largest case series, to our knowledge, of 13 patients with endomyocardial biopsy–proven hydroxychloroquine cardiomyopathy conducted over an 8-year period at one institution. Outcomes after therapy discontinuation varied, ranging from complete resolution to progressive heart failure requiring advanced therapies, including the first reported cases of left ventricle assist device as destination therapy. Early recognition and timely drug cessation may allow for partial or full recovery of cardiac function.

Background

Hydroxychloroquine (HCQ), an antimalarial and antirheumatic agent with immunomodulatory properties, is used as a first-line treatment for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) to reduce disease flare-ups and improve survival 1–3. Cardiomyopathy is a rare but serious adverse effect of long-term HCQ therapy and can manifest as conduction abnormalities and heart failure (HF) 4, 5. The diagnosis depends on electrocardiography, imaging, and histopathologic findings. Here, we describe 13 biopsy-proven cases of HCQ cardiomyopathy identified through a retrospective chart review at our center over an 8-year period and review the existing literature to summarize the clinical features, diagnostic findings, and outcomes in patients with HCQ cardiomyopathy.

Methods

At a single academic medical center, we identified 13 patients with endomyocardial biopsy–proven HCQ cardiomyopathy that met the eligibility requirements for this case series. The study included consecutive patients presenting with HF and pulmonary hypertension (PH) over an 8-year period. A diagnosis was attributed to HCQ when compatible clinical and pathologic findings were identified in patients with documented HCQ exposure exceeding 3 months. A search was conducted in the electronic medical record to identify demographics, pertinent medical history, clinical presentation, cumulative HCQ dose, electrocardiogram (ECG) and transthoracic echocardiogram (TTE) findings, cardiac magnetic resonance imaging (cMRI), and endomyocardial biopsy (EBx) results.

Case Reports

The patients were predominantly female (86%), with ages ranging from 30 to 87 years (mean age 62 years). Patients received cumulative doses ranging from 60 to 3952 g, with an average of approximately 1868 g. The majority presented with progressive dyspnea, with 5 patients being referred for the evaluation of suspected PH. Detailed ECG, TTE, cMRI, and EBx findings are summarized in Tables 1 and 2 and are not restated in the individual case narratives to follow to maintain clarity and brevity. Examples of ECG and cMRI findings are shown in Figures 1 and 2. Findings on TTE varied, with common findings including left ventricular hypertrophy (LVH) 2, diastolic dysfunction 6, and right ventricular dysfunction 6. When performed, cMRI showed delayed hyperenhancement and elevated T1 relaxation times. Endomyocardial biopsies demonstrated myocyte hypertrophy and vacuolization (if reported, typically 20%–30% of myocytes affected), accompanied by mild-to-moderate interstitial fibrosis. Biopsies were assessed for amyloid (Congo red stain), interstitial fibrosis, and vacuolization. The diagnosis of HCQ cardiomyopathy was determined by drug exposure and histologic findings. Electron microscopy was performed in 1 case to evaluate for curvilinear bodies (Figure 3). Alternative causes of vacuolization (for example, Fabry disease, glycogen storage disorders, and doxorubicin exposure) were considered, and final diagnosis was determined on the basis of clinical history, imaging, and pathology.

Once HCQ cardiomyopathy was confirmed via biopsy, HCQ therapy was discontinued. Clinical outcomes varied: 3 patients died—2 after left ventricular assist device (LVAD) implantation and 1 after heart transplantation. Among the remaining patients, 2 achieved complete recovery with normalization of function, 3 showed clinical improvement, and 5 continued to experience dyspnea.

The following cases are organized by initial left ventricular ejection fraction (LVEF) at presentation. Because this study involved only retrospective, deidentified patient information, the requirement for informed consent was waived.

Preserved EF (LVEF ≥50%)

Case 5

A 77-year-old woman with a history of RA receiving HCQ for 14 years as well as having hypertension and restrictive lung disease presented with dyspnea and lower-extremity edema. Findings of EBx suggested a mild degree of cardiac involvement suspected related to long-term HCQ use; therefore, HCQ was discontinued. Clinical improvement was observed, and repeat TTE revealed normal LV size, function, and wall motion, with resolution of previously noted LVH, left atrial enlargement, and grade 2 diastolic dysfunction (DD).

Case 7

A 30-year-old woman with SLE (diagnosed at age 8 years) and systemic scleroderma (diagnosed at age 25 years) on HCQ for 15 years presented with dyspnea and leg cramping. After confirmation by EBx and discussion with rheumatology, HCQ was discontinued. She is asymptomatic now with good functional capacity, although recent TTE demonstrates new LVH and grade 1 DD.

Case 8

A 75-year-old woman with a history of RA on HCQ for 5 months, atrial fibrillation, heart failure with preserved ejection fraction (HFpEF), mild group 2 PH, and severe tricuspid regurgitation presented with dyspnea. After confirmation from EBx, HCQ was discontinued; however, poor exercise tolerance persisted. After the initiation of guideline-directed medical therapy (GDMT) and atrial flutter ablation, she demonstrated clinical improvement with mildly limited functional capacity. Recent TTE demonstrated grade 3 DD and mildly reduced right ventricular (RV) function.

Case 10

A 68-year-old woman with a history of RA on HCQ for 20 years, as well as scleroderma, moderate-to-severe aortic stenosis, and HFpEF presented with PH and worsening dyspnea on exertion. Right heart catheterization (RHC) demonstrated mild PH with an elevated pulmonary capillary wedge pressure. After EBx, HCQ was discontinued and the patient was managed symptomatically with GDMT. She reports ongoing intermittent lightheadedness and dyspnea.

Case 11

A 52-year-old woman with a history of SLE on HCQ for 20 years, as well as end-stage renal disease since age 14 years—secondary to SLE—requiring renal transplant, and HFpEF presented with dyspnea on exertion, edema, palpitations, and chest pain. After confirmation by EBx, HCQ therapy was discontinued, although symptoms have persisted.

Case 12

A 77-year-old woman with a history of RA on HCQ for 10 years, chronic obstructive pulmonary disease, and left bundle branch block was referred for PH evaluation for ongoing dyspnea on exertion, reduced functional capacity, lower-extremity edema, and dizziness worsening over 1 year. Transthoracic echocardiogram demonstrated EF 60% with paradoxical septal motion and grade I diastolic dysfunction (Table 2). After confirmation by EBx, HCQ therapy was discontinued. The patient continues to have ongoing palpitations, lightheadedness, and dyspnea on GDMT.

Reduced EF (LVEF ≤40%)

Case 1

A 65-year-old man with a history of RA on HCQ for 8 years presented with acute decompensated HF. Coronary angiography revealed coronary artery disease (CAD) disproportionate to the degree of left ventricle (LV) dysfunction. After confirmation by EBx, HCQ therapy was discontinued and GDMT was initiated. On follow-up after 3 months, LV systolic function normalized and the patient’s clinical status improved.

Case 2

A 74-year-old woman with a history of RA on HCQ for 30 years, nonischemic cardiomyopathy (NICM) of unclear causes for 1 year, and paroxysmal atrial flutter presented to the hospital with syncope secondary to ventricular tachycardia and decompensated HF with reduced ejection fraction. Transthoracic echocardiogram revealed a reduction from her baseline LVEF of 40% to 25%, and RHC revealed elevated filling pressures and low cardiac output requiring intra-aortic balloon pump and dobutamine support. After confirmation by EBx, HCQ was discontinued. Given the refractory HF, an LVAD was implanted as destination therapy. Early after LVAD implantation, the patient remained in multiorgan failure and the patient’s family requested withdrawal of care.

Case 3

An 87-year-old woman with a history of SLE on HCQ for 27 years, as well as hypertension, paroxysmal atrial fibrillation, and HF with reduced ejection fraction diagnosed 4 months previously presented with worsening dyspnea on exertion of 1 week in duration. Coronary angiography revealed nonobstructive CAD and RHC showed elevated filling pressures with low cardiac output. After EBx confirmation, HCQ was discontinued and GDMT was initiated. On repeat assessment after 3 months, TTE revealed normalization of biventricular function with complete resolution of her symptoms.

Case 4

A 65-year-old man with a history of SLE for 7 years, CAD, and coronary artery bypass surgery 12 years previously, ischemic cardiomyopathy, chronic kidney disease, and diabetes mellitus presented with worsening dyspnea on exertion consistent with decompensated HF. After EBx, HCQ was discontinued. because of refractory HF despite diuresis and inotropes, a HeartMate II LVAD (Abbott) was placed as destination therapy. He had minimal improvement in LV function and died 4 years after device implantation from pump thrombosis.

Case 6

A 59-year-old woman with a history of RA on HCQ for 4 years, as well as hypertension, diabetes mellitus, NICM requiring a cardiac resynchronization therapy defibrillator, paroxysmal atrial fibrillation, and chronic kidney disease stage 3 presented after a mechanical fall resulting in a left intertrochanteric fracture. After EBx, a decision was made to stop HCQ as a potential contributor to NICM. After intervention and management, the patient showed clinical improvement.

Case 9

A 49-year-old woman with a history of SLE on HCQ for 30 years, Raynaud disease, CAD requiring surgical bypass, and ischemic cardiomyopathy presented for advanced HF evaluation and transplant work-up. On RHC, the patient had severe mitral regurgitation and increased pulmonary capillary wedge pressure, with mildly elevated pulmonary vascular resistance. After confirmation by EBx, HCQ was discontinued and the patient received an orthotopic heart transplant. Her hospital course was complicated by multiple surgical-site infections requiring debridements, bacteremia, and eventual multiorgan failure. The patient passed away 7 months after transplant.

Case 13

A 36-year-old woman with a history of SLE on HCQ for 12 years, end-stage renal disease, stage D HF, and previously diagnosed HCQ cardiomyopathy confirmed with EBx presented with progressive dyspnea, orthopnea, and acute hypoxic respiratory failure. On TTE, EF was 45%, although full imaging records were not available. The patient is now being managed on GDMT, with EF further reduced to 20%. She is being considered for advanced therapies, including heart and kidney transplant.

Discussion

Hydroxychloroquine frequently is used for the treatment of rheumatologic diseases, given its track record of safety, efficacy, and tolerability 4, 6. It acts by inhibiting cell-mediated immune reactions 1, 2. Studies estimate that approximately 70% of patients with SLE 7 and 30% of patients with RA 8 receive HCQ therapy long term.

Serious adverse effects such as retinopathy, neuromyotoxicity, and cardiotoxicity have been described with long-term HCQ therapy resulting from its long half-life and accumulation in various organ systems 4, 5, 9. Because of its hydrophobic structure, HCQ binds to phospholipids within lysosomes, causing dysregulation of degradation processes and accumulation of toxic metabolites—visualized as intracellular vacuoles seen on light microscopy and curvilinear bodies seen on electron microscopy imaging 4, 10. Serious adverse effects with HCQ use correlate with the cumulative dose and duration of use 5, with greater rates of cardiac involvement observed at greater cumulative doses 11–13. Underlying patient factors such as genetic polymorphisms and renal and hepatic function are also thought to play a role 4, 5.

The incidence of HCQ cardiotoxicity is not well known because it has only been described in case reports and series. It is reported to have a female predominance 5, 10 and is typically encountered in patients who are between 30 and 80 years of age 4, 5, consistent with our findings. The median time duration of treatment with HCQ associated with HCQ cardiotoxicity has been reported to be 7 years (3 days to 35 years) 14. In this series of 13 patients, the average duration of HCQ treatment was 14 years.

A systematic review of more than 150 cases of antimalarial-induced cardiomyopathy identified decompensated HF, syncope 5, and conduction abnormalities 11, 14 as the most common clinical presentations. Conduction abnormalities occur as a result of the infiltrative nature of this cardiomyopathy 4, 10 and are usually progressive, following a pattern of beginning with right bundle branch block, followed by left anterior fascicular block and complete heart block 4, with approximately 50% of patients requiring a permanent pacemaker 5, 13 (Figure 1). Common laboratory abnormalities include elevation of cardiac enzymes and B-type natriuretic levels 5, 11.

Imaging features are heterogeneous, with TTE findings including LV systolic dysfunction, restrictive diastolic function, LV hypertrophy, biatrial enlargement, and hypertrophy of the interventricular septum 5. Characteristic features on cMRI include patchy delayed hyperenhancement in a noncoronary distribution, elevated T1/T2 values, and involvement of the septum with diffuse or septal fibrosis 5, 15–17 (Figure 2). Resolution of cMRI abnormalities has been reported with the cessation of HCQ therapy 5, which suggests that cMRI could be a potentially useful tool for follow-up, although some cases have demonstrated sustained cMRI abnormalities despite recovery of systolic function, highlighting persistent structural injury 16. The gold standard for establishing the diagnosis is RV EBx, and characteristic histopathology features include intracellular vacuolization on light microscopy and curvilinear bodies on electron microscopy 10, 13, 16 (Figure 3). The clinical, electrocardiographic, and imaging features of the patients in our series are detailed in Tables 1 and 2.

The differential diagnosis for HCQ cardiomyopathy includes infiltrative and genetic cardiomyopathies such as amyloidosis, sarcoidosis, Fabry disease, and hypertrophic cardiomyopathy due to overlapping imaging and histopathologic features. In this study, only patients receiving HCQ with suspected HFpEF underwent EBx. The majority were female, rendering X-linked recessive disorders such as Fabry disease less likely. Furthermore, none demonstrated significant LVH on cMRI or TTE, a finding more commonly associated with Fabry disease than with HCQ-induced cardiomyopathy. Alternative diagnoses were not systematically excluded, but rather the coexistence of long-standing HCQ exposure and biopsy-proven vacuolization was considered sufficient to justify discontinuation of HCQ, given the perceived risk for ongoing toxicity. Continuation of HCQ treatment while pursuing additional testing for rare causes of vacuolization, such as genetic evaluation for Fabry disease, was not deemed clinically appropriate. However, the absence of HF improvement after greater than 6 months of HCQ cessation would have strengthened the indication for further etiologic evaluation, which constitutes a limitation of this study.

Data to guide the management of HCQ cardiotoxicity are limited. After the diagnosis is established, it is important to discontinue HCQ and initiate GDMT for HF. Outcomes are variable and can range from a complete resolution of the cardiomyopathy, progression of HF requiring advanced therapies, or death (5, 10, 12, 18, 19). Predictors of favorable outcomes are not well understood. In a systematic review of 127 patients with antimalarial cardiotoxicity, HCQ was discontinued in 78 patients, of whom 45% had recovery of cardiac function and 31% died (14). To our knowledge, our series is the first to report the use of LVAD as destination therapy. Mortality ranges from 30% to 45% based on a review of existing literature (5, 14).

HCQ cardiomyopathy is an underrecognized condition related to long-term HCQ therapy with greater cumulative doses. Clinicians should maintain a high index of suspicion in patients with PH or HF phenotypes and prolonged HCQ use, because cessation of therapy might allow for recovery of cardiac function. When medical therapy fails, LVAD implantation may serve as destination therapy for carefully selected patients. Cardiac biomarkers, electrocardiogram, TTE, and cMRI can serve as screening tools, whereas RV EBx can establish the diagnosis. Larger studies are required to better understand the prevalence and reversibility of this disease with early intervention.