|INTERESTING CASE REPORT
|Year : 2023 | Volume
| Issue : 1 | Page : 31-36
Effectiveness and Safety of Sacubitril/Valsartan for Heart Failure with Reduced Ejection Fraction Secondary to Duchenne Muscular Dystrophy-Associated Cardiomyopathy
Pankaj Jariwala, Kartik Jadhav, Saket Khetan
Department of Cardiology, Yashoda Hospitals, Hyderabad, Telangana, India
|Date of Submission||11-Apr-2022|
|Date of Decision||23-Jun-2022|
|Date of Acceptance||05-Jul-2022|
|Date of Web Publication||28-Nov-2022|
Dr. Pankaj Jariwala
Department of Cardiology, Yashoda Hospitals, Somajiguda, Raj Bhavan Road, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
In individuals with an ejection fraction of 40% or less, the use of sacubitril/valsartan significantly lowers mortality or hospitalization. There has been no research related to the effectiveness and safety of sacubitril/valsartan in patients with Duchenne muscular dystrophy (DMD)-associated cardiomyopathy. We hereby report a case of DMD-associated cardiomyopathy and heart failure with reduced ejection fraction who had been on routine guideline-directed medical treatment with no change in clinical or echocardiographic markers. When guideline-directed medical therapy was unsuccessful, sacubitril/valsartan was started which resulted in a significant change in functional class and significant ventricular remodeling, including an improvement in left ventricular (LV) ejection fraction, reduction in LV diastolic diameter, and a reduction in mitral regurgitation.
Keywords: Angiotensin antagonist, dilated cardiomyopathy, heart failure with reduced ejection fraction, muscular dystrophy
|How to cite this article:|
Jariwala P, Jadhav K, Khetan S. Effectiveness and Safety of Sacubitril/Valsartan for Heart Failure with Reduced Ejection Fraction Secondary to Duchenne Muscular Dystrophy-Associated Cardiomyopathy. J Indian Acad Echocardiogr Cardiovasc Imaging 2023;7:31-6
|How to cite this URL:|
Jariwala P, Jadhav K, Khetan S. Effectiveness and Safety of Sacubitril/Valsartan for Heart Failure with Reduced Ejection Fraction Secondary to Duchenne Muscular Dystrophy-Associated Cardiomyopathy. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2023 [cited 2023 May 29];7:31-6. Available from: https://jiaecho.org/text.asp?2023/7/1/31/362191
| Introduction|| |
It is progressive cardiomyopathy that causes severe morbidity and death in patients with Duchenne muscular dystrophy (DMD). There is a wide range of severity and age at which dilated cardiomyopathy (DCM) develops in DMD. DMD has less ventricular dilation than other kinds of DCM, which begins with dysfunction without dilation. Earlier studies have indicated that cardiac dysfunction increases with age and the degree of skeletal muscle degeneration in DMD patients.
Patients with DMD are benefiting greatly from advances in skeletal muscle and respiratory treatment. However, even though more individuals are surviving into their late 30s because of novel therapeutic modalities, heart failure (HF) and cardiac mortality have increased throughout this period. For individuals with DMD, cardiac treatment focuses on monitoring and management, intending to prevent or delay HF. Noninvasive imaging of heart function and pharmacological treatment are among the latest cardiac recommendations.
A study called Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF (PARADIGM-HF) recently compared sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI) with enalapril, an angiotensin-converting enzyme inhibitor (ACEi) to see how they affected overall mortality and morbidity of patients with HF with reduced ejection fraction (HFrEF). The study randomly assigned 8399 people to treatment with enalapril or with sacubitril/valsartan. Sacubitril/valsartan reduced cardiovascular mortality or HF-hospitalization by 20% when compared to enalapril.
The role of sacubitril/valsartan in DMD-associated cardiomyopathy has not been adequately studied so far. The studies of HF evaluating the effectiveness and safety of sacubitril/valsartan did not necessarily exclude patients with DMD just because of their diagnosis, but mostly because of DMD-related comorbidities and unfavorable lab results. In this case report, we describe the use of sacubitril/valsartan in a patient with DMD-associated HFrEF and discuss the clinical perspectives related to the same.
| Case Report|| |
A 24-year-old male, a known case of DMD who was wheelchair confined, was hospitalized for dyspnea at rest and orthopnea in September 2019. Clinical examination revealed a pulse rate of 104 beats per min, blood pressure 100/60 mmHg, and signs of systemic congestion in the form of raised jugular venous pressure, bilateral pedal edema, and basal rales on auscultation. On cardiovascular examination, there were parasternal pulsations with a heave, and the left ventricular apex shifted downward and laterally to the 6th intercostal space. There was an S3 gallop with muffled heart sounds and no murmur. Electrocardiography revealed sinus tachycardia with the poor progression of “R-wave” with left axis deviation. Echocardiography showed a dilated left ventricle (LV) with global hypokinesia with LV ejection fraction (LVEF) 25%. It also showed severe mitral regurgitation with grade III diastolic dysfunction, indicating high left atrial pressure [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f, [Figure 1]g, [Figure 1]h, [Figure 1]i, [Figure 1]j, along with high systolic pulmonary artery pressure (60 mmHg), right atrial and ventricular dilatation, and dysfunction. A clinical diagnosis of DMD-associated cardiomyopathy with HFrEF with American College of Cardiology/American Heart Association stage C was made. Laboratory parameters showed normal hemogram, normal renal parameters, but mildly elevated liver enzymes (alanine aminotransferase 110 IU/L, aspartate aminotransferase 68 IU/L) and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP, 6789 pg/mL).
|Figure 1: Transthoracic echocardiography in four-chamber (a) and parasternal (b) views demonstrated dilation of all the cardiac chambers including the left atrium (5.44 cm) and LV (6.36 cm × 5.35 cm; end-diastolic volume – 206 ml; end-systolic volume – 138 ml), the LV ejection fraction was 33% by Teicholz method (c). The global longitudinal strain calculated using speckle tracking analysis was 9.5% with a calculated LV ejection fraction of 30% (d). The color flow mapping of the mitral valve revealed severe mitral regurgitation with a mitral jet area of 13.3 cm2 (e). The pulsed-wave Doppler interrogation of the mitral inflow showed grade III diastolic dysfunction (f). The tissue Doppler measurements obtained at the basal septum showed systolic dysfunction, and the calculated E/E' was 15 suggestive of elevated left ventricular end-diastolic pressure (g). The continuous-wave Doppler interrogation of the tricuspid regurgitation demonstrated low-pressure regurgitation with right ventricular systolic pressure of 21 + 20 mmHg (h). The inferior vena cava was distended with no respiratory variations (i). The LV longitudinal strain polar map showed impaired global function with more marked impairment of the basal and anterior segments (j). E: Early diastolic mitral inflow velocity, E': Early diastolic mitral annular velocity, LV: Left ventricle|
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The patient had been receiving carvedilol 12.5 mg twice daily, ivabradine 5 mg twice daily, ramipril 5 mg twice daily, spironolactone 25 mg once daily, furosemide 40 mg twice daily, digoxin 0.25 mg once daily for 5 days in a week, and the fixed-dose combination of hydralazine and isosorbide mononitrate thrice daily. His condition was stabilized with the escalation of the diuretic dose and administration of intravenous milrinone for 48 h.
Despite medical treatment optimized according to guidelines, his clinical condition showed a waxing waning course over the next 18 months, although echocardiographically he remained stable (LVEF 32% in March 2021) and NT-proBNP had declined to a trough of 876 pg/mL. However, his clinical state worsened by the time of his 6th follow-up visit. He was experiencing increasing dyspnea and fatigue during his routine activities, and NT-proBNP level again rose to 4567 pg/mL. At this point, ramipril was replaced with sacubitril/valsartan, beginning at 50 mg twice daily and then up-titrated to 100 mg twice daily after 30 days. All other drugs were kept at the same dosages.
The patient showed clinical improvement with no breathlessness at rest or during his routine wheelchair-bound activities in May 2021. His echocardiogram revealed evidence of reverse remodeling, with better LV parameters, an ejection fraction of 45%, and trivial mitral and tricuspid regurgitation [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f, [Figure 2]g. The NT-proBNP level also declined and was at its lowest (566 pg/mL) ever recorded in him. During the following 6 months, by the time of the last follow-up visit in January 2022, he continued to show improvement in his clinical situation.
|Figure 2: Transthoracic echocardiography during follow-up in the same patient as in Figure 1. There was a reduction in the size of all cardiac chambers including left atrium and ventricle (5.7 cm × 4.0 cm; end-diastolic volume – 161 cm; end-systolic volume – 72.5 ml), with the calculated LV ejection fraction of 55% (a and c). The color flow mapping of the tricuspid valve revealed trivial tricuspid regurgitation with normal pulmonary artery pressure (b). The mitral inflow velocities showed grade I diastolic dysfunction (d). Tissue Doppler imaging demonstrated normal LV systolic and diastolic functions (e). The speckle tracking echocardiography showed that the global longitudinal strain of the LV had improved to 19.7% (f). The polar map demonstrated improvement in the regional function of the LV basal and apical segments (g). LV: Left ventricle|
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| Discussion|| |
DMD is an X-linked recessive dystrophinopathy caused by a dystrophin gene mutation. Around 3000 mutations in the dystrophin gene have been associated with DMD, with deletions accounting for 70% of all variations, duplications accounting for 5%, and point mutations accounting for the remaining 25%. The deficiency of dystrophin leads to muscle degeneration, necrosis, and atrophy, which in turn leads to progressive skeletal myopathy., A reduction in dystrophin expression causes skeletal muscle degeneration and regeneration. Muscle regeneration potential diminishes with age owing to a decline in the lifetime of myogenic progenitor cells and skeletal myoblasts. Consequently, the periodic processes of muscle regeneration and degeneration cause muscle wasting and atrophy. The illness manifests clinically as difficulty in walking during early adolescence, a restrictive lung disease caused by diaphragmatic weakness, and scoliosis.
The loss of dystrophin in cardiomyocytes causes cell death and cardiac fibrosis that eventually result in HFrEF in patients with DMD. It has been shown that the DMD patients' genotype may predict the severity of their cardiomyopathy. DCM is the most frequent form of cardiac involvement in DMD, and it may manifest itself at any age and with any degree of severity. Several studies have shown that the majority of DMD patients develop cardiomyopathy before the age of 18. Patients with DMD are more likely to die from heart disease than any other cause, and earlier research has indicated that heart disease worsens with age and the severity of skeletal muscle illness. Because of skeletal muscle dysfunction, early indicators of HF may not be visible to the naked eye. Patients with DMD and mild late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) tend to show considerably higher troponin I levels in their blood than those without LGE. Troponin I levels in DMD cardiomyopathy may thus be useful as a noninvasive marker for following the development of early heart disease and characterizing the damage that has occurred.
Echocardiography and CMR are among important diagnostic imaging modalities to identify decreased heart function or dilated LV., Echocardiography reveals regional wall abnormality involving the basal segment of the LV posterior wall, LV dilatation, and decreased LV systolic function in DMD-associated cardiomyopathy. Because DMD patients have decreased LV global circumferential and longitudinal strain, strain imaging offers a good diagnostic yield for the early identification of myocardial fibrosis in these patients. Early detection of myocardial fibrosis is enabled by the changes in global strain pattern at an early stage. Micro-fibrosis has been seen throughout the heart, demonstrating an abnormal global strain pattern as a marker of subclinical involvement. Echocardiographic screening is now considered necessary in DMD, at the time of diagnosis or by the age of 6 years, with follow-up every 2-3 years until the patient is 10 years old. However, chest wall abnormalities, scoliosis, and respiratory dysfunction often restrict the diagnostic yield of echocardiography in DMD, which is otherwise a simple, quick, and inexpensive diagnostic tool.
CMR is rapidly becoming the gold standard for assessing cardiac structure and function in DMD patients. The size and function of the LV may be measured using CMR. A yearly or biennial CMR may identify cardiomyopathy in patients as young as ten. Even in those with normal LV function, CMR may reveal LGE. Pulchalski et al. studied 74 DMD patients and observed that the majority of the patients showed LGE in the posterobasal area of the LV, with a subepicardial distribution pattern. Hagenbuch et al. used serial circumferential strain measurements to examine cardiac dysfunction in DMD patients. They showed that circumferential strain could detect DMD-related cardiac dysfunction even before the onset of HF.
Improvements in non-cardiac management of DMD has resulted in DCM becoming an increasingly important cause of morbidity and mortality in these patients. Hence, early detection of myocardial abnormalities and treatment to improve ventricular remodeling are essential to improve cardiac outcomes and quality of life. Unfortunately, identifying traditional HF symptoms in a patient who is unable to walk might be challenging. Therefore, the Center for Disease Control and Prevention 2018 DMD Care Considerations recommend that the patients with DMD should have regular cardiac examinations.
More than 70% of DMD patients are above the age of 18 when the preclinical cardiac changes tend to manifest as clinically overt cardiac disease such as conduction abnormalities, DCM, and hypertrophic cardiomyopathy that may advance toward DCM. Supraventricular and ventricular arrhythmias are hallmarks of HF that results from the cardiomyopathy associated with DMD. Sinus tachycardia also quite common and may worsen HF symptoms by decreasing cardiac output. HF patients are at a higher risk for ventricular arrhythmia and sudden cardiac death. Common causes of symptomatic bradycardia include sinus node dysfunction and atrioventricular block.
Patients with DMD who are experiencing obvious cardiac problems currently have no curative options. Personalized disease management may be improved by proactive diagnosis and precise genetic investigation. Effective treatment requires novel or combined approaches that have clinical utility. Despite successful DMD-associated cardiomyopathy therapy, all DMD patients tend to die before the age of 45. Clustered regularly interspaced short palindromic repeats/Cas9 genome editing is likely to be a therapeutic option for many persons with DMD. However, while this novel treatment will convert DMD patients to Becker muscular dystrophy patients, it will not cure the disease. Many of these patients will continue to be at high risk of developing irreversible HF.,
Tandon et al. used cardiac MRI images to evaluate the effects of steroid use in a large, single-center DMD cohort. As time passes, LGE anomalies will only get worse, and steroid use has been linked in retarding the changes in LGE positive cardiac areas. Further research is required to determine whether long-term steroid medication protects against cardiac damage caused by survival into the late adulthood.,
Eplerenone, a mineralocorticoid receptor antagonist, was shown to be more effective when combined with an ACEi in DMD patients than the ACEi alone in terms of slowing down the deterioration in LV function after 2 years. Beta-adrenergic blockers are another useful option and the Care Considerations and the American Heart Association guidelines advocate their use in patients with persistent LV dysfunction or elevated heart rate.,
Sacubitril/valsartan is a first-in-class ARNI that concurrently inhibits neprilysin and blocks the renin–angiotensin–aldosterone system, correcting the imbalance of neurohumoral mediators. In patients with HFrEF, the PARADIGM-HF trial found that sacubitril/valsartan outperformed enalapril (an ACEi) in terms of clinical outcomes. It resulted in a 20% reduction in cardiovascular death and a 16% reduction in all-cause mortality when compared with enalapril. HF hospitalizations were also reduced by 20%. Furthermore, as compared with enalapril, sacubitril/valsartan was well tolerated. Sacubitril/valsartan patients were less likely than enalapril patients to drop out of the trial early because of adverse events (10.1% vs. 12.3%, P = 0.03). Enalapril had higher rates of renal impairment, hyperkalemia, and cough than sacubitril/valsartan. However, sacubitril/valsartan had a greater risk of hypotension than enalapril, although the number of hypotension patients documented as significant adverse events was similar. Even though sacubitril/valsartan had a statistically higher risk of angioedema than enalapril (0.45% vs. 0.24%), the overall risk was quite low.
There has only been a very limited experience of using sacubitril/valsartan in DMD-associated DCM., The use of this drug in DMD patients could present several potential challenges, as summarized in [Table 1].
|Table 1: The summary of the challenges and evidence about the use of angiotensin receptor-neprilysin inhibitor in the Duchenne muscular dystrophy-associated cardiomyopathy|
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Our patient tolerated sacubitril/valsartan quite well, despite the reported risk of severe hypotension according to one case report. Lamendola et al. followed-up three patients with DMD-associated cardiomyopathy, and the findings showed a significant increase in LVEF after a year of follow-up, similar to what was observed in our case also. There were no notable adverse effects observed throughout the study. Furthermore, Papa et al. reported a patient with end-stage DCM with severe LV dysfunction caused by dystrophinopathy (Becker muscular dystrophy) who responded effectively to ARNI. However, so far, there have been no published large-scale studies on the use of ARNI in patients with DMD-associated cardiomyopathy, and no conclusive evidence to support this. Further research on the topic is required to address these issues.
| Conclusion|| |
Due to early-life proliferative anomalies caused by dystrophin deficiency, individuals with DMD are often born with underdeveloped hearts. Hearts of patients with DMD tend to enlarge with time, leading to complications and death from end-stage cardiomyopathy. Patients with DMD have benefited greatly from advances in non-cardiac treatment over the past several decades. As a result, cardiomyopathy is now becoming an increasingly common cause of morbidity and mortality in these patients. Since a multiparameter cardiac examination has become the standard of care now-a-days, the rationale for early initiation of cardiac treatment in DMD is also evolving. At the same time, newer drugs such as ARNI have also become available, which significantly improve HF outcomes. In view of this, clinical trials are now needed to define the optimum management strategy, focusing on prevention and treatment of HF, in patients with DMD.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]