Left ventricular noncompaction (LVNC) is characterized by prominent left ventricular trabeculae, deep intertrabecular recesses and thin compacted layer . The most common and clinically significant feature of LVNC is heart failure with reduced ejection fraction (HFrEF), for which there is no specific treatment. Here, we report a case of LVNC that responded favorably to sacubitril-valsartan treatment. Left ventricular ejection fraction (LVEF) based on cardiac magnetic resonance imaging (CMRI) improved by 25% with features suggestive of reverse modeling after 16 months of treatment.
A 58-year-old woman presented to the emergency department with progressively aggravated dyspnea after physical activities for 4 months. Over the past 4 years, she has been receiving various treatments for HFrEF (as low as 27%), including metoprolol 47.5 mg/day, benazepril 10 mg/day, torasemide 20 mg/day, spirolactone 20 mg/day, and digoxin 0.25 mg/day, but her clinical conditions and echocardiographic parameters remained poor. She denied history of smoking, alcohol abuse, hypertension, diabetes, and coronary/valvular heart diseases. Upon presentation, blood pressure was 132/90 mm Hg, heart rate was 106/min, and respiratory rate was 32/min. On physical examination, moist rales were audible in lower lungs in both sides and pitting edema was noted in both feet. Laboratory studies revealed a brain natriuretic peptide level of 1310 pg/mL. Electrocardiogram revealed premature ventricular beats and intraventricular block (Figure 1). She was treated with 40 mg torasemide to reduce the cardiac preload in the emergency room, and then transferred to the Heart Failure Unit.
A chest computed tomography next day showed no significant lung congestion. Twenty-four hours Holter monitoring recorded a total of 3382 premature ventricular beats. A transthoracic echocardiogram (ECHO) showed a severely enlarged left ventricle (Figure 2A and B) with a reduced LVEF of 26% (Simpson), severe diastolic dysfunction (E/é >15, Class IV) (Figure 3A), and features of LVNC (Figure 3B and C). CMRI confirmed left ventricular noncompaction (Figure 4A and B). The ratio versus compacted myocardium was >2.3 overall, and as high as 3.9 in the inferior lateral wall of the LV at the end-diastolic phase. The LVEF was 24%.
Considering the poor response to previous treatment, sacubitril-valsartan 50 mg twice a day was added to guideline-recommended treatment (β-blocker, torasemide, spirolactone, digoxin, and isosorbide mononitrate). Symptoms and signs improved rapidly, and the patient was discharged 1 week later. Discharge prescription included spirolactone 20 mg, metoprolol 47.5 mg, and sacubitril-valsartan 50 mg twice a day. A follow-up 4 weeks after discharge indicated unsatisfactory blood pressure control, and sacubitril/valsartan was adjusted to 100 mg twice daily. All other drug treatments remained unchanged. Regular follow-up during the following 12 months showed good control of blood pressure (90–120/50–70 mm Hg) and resting heart rate (45–55/min). An ECHO examination 16 months later demonstrated a significantly smaller cavity of the heart and improved LV systolic (EF 51%) and diastolic (10<E/é<14, Class II) function (Figures 2C and D and 3D). CMRI showed significantly reduced ratio of 2.8 in noncompacted versus compacted myocardium (Figure 4C and D). The details of the patient's process of diagnosis and treatment are shown in Table 1.
|Four years before presentation
||Symptoms and signs of heart failure, including dyspnea and lower limb edema. No conditions other than LVNC (eg, coronary artery disease) were noted. She received guideline-recommended treatment for HFrEF (27%).
|Four months before presentation
||Progressively aggravated shortness of breath
|First day at the emergency department
||Moist rales were audible over both lower lungs and bilateral pitting edema was noted in both feet. Brain natriuretic peptide level of 1310 pg/mL. She received torasemide to reduce the preload.
|First day in Heart Failure Unit.
||ECHO showed a severely enlarged LV with 26% LVEF and class IV diastolic dysfunction (E/é >15). In CMRI, LVEF was 24%, and the non-compacted to compacted ratio was >2.3 (3.9 in the inferior lateral wall of the LV end-diastolic phase).
|First week in Heart Failure Unit.
||The patient was managed with β-blocker, torasemide, spirolactone, digoxin, isosorbide mononitrate and sacubitril-valsartan. Symptoms improved substantially and she was discharged in 1 week. Discharge prescription included spirolactone 20 mg, metoprolol 47.5 mg and sacubitril-valsartan 50 mg twice a day.
||Sacubitril/valsartan was adjusted to 100 mg twice daily,
||Resting heart rate: 45–55/min; blood pressure: 90–120/50–70 mm Hg.
||No symptoms and signs of HF. ECHO demonstrated significantly smaller heart chamber and 51% LVEF and class II diastolic function. CMRI showed significantly reduced ratio of 2.8 in noncompacted versus compacted myocardium
CMRI: cardiac magnetic resonance imaging; HFrEF: heart failure with reduced ejection fraction; LV: left ventricular; LVEF: left ventricular ejection fraction; LVNC: left ventricular noncompaction.
Discussion and conclusions
LVNC is believed to be the result of stagnation of densification caused by myocardial developmental defects. The LV apical myocardium is the last area that undergoes densification and thus is always involved. Clinical manifestations of LVNC typically include HF, conduction abnormalities, tachycardia, and sudden death. The most common presentation at admission is pump failure. Congestive HF of LVNC could appear as either HFrEF, systolic dysfunction or HF with preserved ejection fraction (HFpEF) and diastolic dysfunction. In more recent reports, HFrEF and marked systolic dysfunction are common[4,6].
LVNC is mainly diagnosed by imaging, including ECHO, CMRI, and LV angiography with ventriculography. CMRI could display the trabeculae at the end-diastolic phase with high resolution and accurately assess the extent of trabecular enlargement, which in turn carries important prognostic significance. The ratio of noncompacted versus compacted myocardium in the index cases was >2.3, and as high as 3.9 in the inferior lateral wall of the LV in the end-diastolic phase, meeting the diagnostic criteria proposed by Petersen and colleagues.
There is no specific therapy for LVNC. Management is based on complications, including HF, thromboembolic events and arrhythmia. For symptomatic patients with HF, the ACC/AHA guideline recommends the use of diuretics, β-blockers and angiotensin-converting enzyme inhibitors. A small retrospective study reported smaller LV mass in patients taking versus not taking β-blockers, but no improvement in LVEF and ECHO parameters. The lack of clinical response and ECHO improvement in the index case during the 4-year period prior to presenting to us with β-blockers, torasemide, spirolactone, and digoxin is consistent with the previous report.
Both angiotensin receptor antagonism by valsartan and neprilysin inhibition by sacubitril could result in a set of beneficial responses, including vasodilatation, water, and sodium excretion and reverse ventricular remodeling. In the PARADIGM-HF study, sacubitril-valsartan reduced the relative risk of cardiovascular death or hospitalization by 20% in HFrEF patients. Interestingly, subgroup analysis in the PARADIGM-HF study indicated treatment benefit across various disease etiologies. In the PROVE-HF study, 12-month sacubitril-valsartan treatment was associated with 9.4% increase in LVEF as well as significant reductions in LV end-diastolic volume index (LVEDVI) and LV end-systolic volume index (LVESVI). In the index case, long-term sacubitril-valsartan treatment resulted in robust and sustained increase in LVEF and decrease in LVEDVI and LVESVI. Clinically significant improvement in left atrial volume index and ratio of early transmitral doppler velocity/early diastolic annular velocity (E/é) was also observed.
Sacubitril-valsartan has been shown to alleviate myocardial fibrosis in animal models. In the index patient, the ratio of non-compacted to compacted LV in the short-axis view of the end-diastolic stage at 16 months after treatment was 2.8, which was lower than upon presentation. The result suggested possible reversal of myocardial remodeling, which in turn has been associated with improved long-term outcomes.
In conclusion, the robust and sustained hemodynamic improvement and reduced ratio of noncompacted to compacted myocardium in this case suggested possible reverse remodeling in LVNC with sacubitril-valsartan treatment although cause-effect relationship is far from clear.
Cost of MRI and ECHO examinations was provided by the fund of Shanghai Sailing Program (Grant Number: 20YF1450300). Travel expenses for patient follow-up were provided by the fund of the Key Project of Yueyang Hospital (Grant Number: 2019YYZ03).
YWY wrote the manuscript. JY and JFX performed the imaging examination and participated in collecting data. MF revised the manuscript. All authors reviewed and approved the manuscript.
Conflict of interest statement
The authors declare that they have no financial conflict of interest with regard to the content of this report.
. Towbin JA, Lorts A, Jefferies JL. Left ventricular non-compaction cardiomyopathy. Lancet 2015;386(9995):813–825. doi:10.1016/S0140-6736(14)61282-4.
. Arbustini E, Favalli V, Narula N, et al. Left ventricular noncompaction: a distinct genetic cardiomyopathy? J Am Coll Cardiol 2016;68(9):949–966. doi:10.1016/j.jacc.2016.05.096.
. Oechslin E, Jenni R. Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? Eur Heart J 2011;32(12):1446–1456. doi:10.1093/eurheartj/ehq508.
. Salazar-Mendiguchía J, González-Costello J, Oliveras T, et al. Long-term follow-up of symptomatic adult patients with noncompaction cardiomyopathy. Rev Esp Cardiol (Engl) 2017;72(2):169–171. doi:10.1016/j.rec.2017.11.021.
. Arenas IA, Mihos CG, Yeh DD, et al. Echocardiographic and clinical markers of left ventricular ejection fraction and moderate or greater systolic dysfunction in left ventricular noncompaction cardiomyopathy. Echocardiography 2018;35(7):941–948. doi:10.1111/echo.13873.
. Ikeda U, Minamisawa M, Koyama J. Isolated left ventricular non-compaction cardiomyopathy in adults. J Cardiol 2015;65(2):91–97. doi:10.1016/j.jjcc.2014.10.005.
. Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113(14):1807–1816. doi:10.1161/CIRCULATIONAHA.106.174287.
. Zuccarino F, Vollmer I, Sanchez G, et al. “Left ventricular noncompaction: imaging findings and diagnostic criteria”. Am J Roentgenol 2015;204:519–530. doi:10.2214/AJR.13.12326.
. Anderson RH, Jensen B, Mohun TJ, et al. Key questions relating to left ventricular noncompaction cardiomyopathy: is the emperor still wearing any clothes? Can J Cardiol 2017;33(6):747–757. doi:10.1016/j.cjca.2017.01.017.
. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:147–239. doi:10.1016/j.jacc.2013.05.019.
. Li J, Franke J, Pribe-Wolferts R, et al. Effects of β-blocker therapy on electrocardiographic and echocardiographic characteristics of left ventricular noncompaction. Clin Res Cardiol 2015;104:241–249. doi:10.1007/s00392-014-0778-z.
. Hubers SA, Brown NJ. Combined angiotensin receptor antagonism and neprilysin inhibition. Circulation 2016;133(11):1115–1124. doi:10.1161/CIRCULATIONAHA.115.018622.
. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. New Engl J Med 2014;371(11):993–1004. doi:10.1056/NEJMoa1409077.
. Januzzi JL Jr, Prescott MF, Butler J, et al. Association of change in N-Terminal pro-b-type natriuretic peptide following initiation of sacubitril-valsartan
treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. J Am Med Assoc 2019;322(11):1–11. doi:10.1001/jama.2019.12821.
. Ai J, Shuai Z, Tang K, et al. Sacubitril/valsartan alleviates myocardial fibrosis in diabetic cardiomyopathy rats. Hellenic J Cardiol 2021;62(5):389–391. doi:10.1016/j.hjc.2021.04.004.
. Chang HY, Chen KC, Fong MC, et al. Recovery of left ventricular dysfunction after sacubitril/valsartan: predictors and management. J Cardiol 2020;75:233–241. doi:10.1016/j.jjcc.2019.08.005.