Isolated left ventricular noncompaction in adults: Management and prognosis

INTRODUCTION — Left ventricular noncompaction (LVNC) is a distinct phenotype characterized by prominent LV trabeculae and deep intertrabecular recesses [1,2]. LVNC was previously also called spongy myocardium or hypertrabeculation syndrome but these terms should not be used interchangeably with LVNC [3].

This review will focus on management of LVNC as an isolated disorder distinct from other clinical settings in which noncompacted myocardium may be seen in association with other cardiac and non-cardiac abnormalities. Clinical manifestations and diagnosis of LVNC and the classification of cardiomyopathies are discussed separately. (See "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis" and "Definition and classification of the cardiomyopathies".)

GENERAL MANAGEMENT

Monitoring — We suggest routine annual clinical evaluation, 12-lead electrocardiogram (ECG), and transthoracic echocardiography in adults with LVNC. More frequent follow-up with clinical evaluation and echocardiography is recommended in patients with new or worsening cardiac symptoms or signs. (See "Tests to evaluate left ventricular systolic function".)

Since patients with LVNC are at risk for atrial and ventricular arrhythmias, we also suggest annual ambulatory continuous (Holter) 48-hour or other prolonged ECG monitoring to detect asymptomatic arrhythmias. The utility of ambulatory ECG monitoring in this setting has not been established. Varying rates of arrhythmia have been detected by ambulatory ECG monitoring as illustrated by the following two studies. A study including 45 patients with LVNC (mean age 37 years), revealed nonsustained ventricular tachycardia in 20 percent [4]. In a study of 72 patients less than 21 years old with LVNC undergoing 126 Holter ECGs, frequent ventricular arrhythmias were found in 6 percent and nonsustained ventricular tachycardia in 2 percent of Holter examinations [5].

Exercise — The following recommendations are similar to those in the 2015 American Heart Association/American College of Cardiology (AHA/ACC) scientific statement on recommendations for competitive athletes, and the 2019 Position Statement of the European Association of Preventive Cardiology (EAPC) given the limited available evidence [6,7]:

●For asymptomatic patients with LVNC and normal systolic function without significant ventricular tachyarrhythmias on ambulatory monitoring or exercise testing, and no prior history of unexplained syncope, competitive sports, with the exception of sports in which occurrence of syncope may cause serious harm or death (such as rock climbing, scuba diving, or car/motor racing), may be considered.

●Athletes with a definite diagnosis of LVNC and impaired systolic function or significant atrial or ventricular tachyarrhythmias on ambulatory ECG monitoring (Holter) or exercise testing and those with a history of syncope should not participate in competitive sports, with the possible exception of low-intensity class 1A sports (figure 1).

Genetic testing and family screening — All patients with LVNC require family and genetic counseling [8]. Given the limited specificity of criteria for LVNC, the 2018 Heart Failure Society of America (HFSA) guideline on genetic evaluation of cardiomyopathy limited application of its LVNC recommendations to only those with the most prominent disease. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Genetic evaluation of cardiomyopathy'.)

We agree with the 2018 HFSA guideline recommendation for careful family history for at least three generations and screening first-degree relatives of patients diagnosed with LVNC [8]. Clinical screening should include history, physical examination, ECG, echocardiogram, and creatine kinase at initial evaluation only. At-risk first-degree relatives with any abnormal screening tests are potential candidates for repeat clinical screening at one year. Asymptomatic first-degree relatives with negative initial screening should be rescreened at three- to five-year intervals beginning in childhood (starting with three-year intervals) or any time symptoms or signs appear.

We recommend genetic studies in patients and families with LVNC [9]. The 2018 HFSA guideline suggests genetic testing for the one most clearly affected person in a family to facilitate family screening and management [8]. If a proband with LVNC has a disease-causing gene variant, first-degree relatives should undergo clinical screening for the disease along with genetic counseling and genetic testing [9]. In LVNC, genetic testing is superior to clinical testing and imaging studies, as in other cardiomyopathies.

The limits of conventional imaging are demonstrated by the 12 times higher prevalence of LVNC using cardiovascular magnetic resonance (CMR) imaging compared with echocardiography [10]. LVNC is a real entity; however, distinguishing physiological adaptation of increased trabeculations without thinning of the noncompacted myocardium (as seen in pregnant patients and in athletes) from pathology causing adverse cardiovascular events requires new approaches for quantification and multiparametric models that consider genetic and clinical variables in addition to morphology [11].

Routine genetic testing in patients with LVNC is recommended based on the following data:

●A multicenter study from the Netherlands classified 327 unrelated patients with LVNC into three categories: genetic (with an identified mutation), probably genetic (familial cardiomyopathy without an identified mutation), and sporadic (no family history and no identified mutation) [12]. In the genetic LVNC group, the most common mutations were MYH7, MYBPC3, and TTN mutations (71 percent).

•The prevalence of reduced LV ejection fraction (LVEF) was higher for genetic LVNC compared with probable genetic and sporadic cases with the highest risk in patients with multiple mutations and TTN mutations.‬‬‬‬‬‬

Mutations were more frequent in children and were associated with major adverse cardiac events (MACE). Adults were more likely to have sporadic LVNC.

•High risk for cardiac events in children and adults was related to LV systolic dysfunction in patients carrying a mutation, but not in sporadic cases. Patients with LVNC and MYH7 mutations had a low risk of MACE.‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬

●In a study including 113 families of 143 LVNC index patients, genetic analysis helped to identify the phenotype and added to prognostic information [13]. Among the 216 individuals diagnosed with LVNC, 43 percent had isolated LVNC; this presentation was associated with a milder course and mutations in the head of MYH7. Fifty-three percent had LVNC with dilated cardiomyopathy phenotype (LV dilation), which was associated with LV systolic dysfunction, increased risk of major adverse cardiac events, and mutations in the tail of MYH7. The remaining 4 percent had LVNC with hypertrophic cardiomyopathy (HCM) phenotype, which was associated with MYBPC3 and HCM without LVNC in relatives.

‬‬‬‬‬‬‬

Pregnancy — Management of women with LVNC contemplating pregnancy includes preconception counseling regarding potential maternal and fetal risks (including the risk of disease transmission). Management during pregnancy is similar to that for other patients with cardiomyopathy, heart failure (HF), or risk of HF [14]. The CARPREG or WHO Risk Score is helpful in pre-pregnancy risk stratification in LVNC [15]. Death and embolic events are very rare. (See "Management of heart failure during pregnancy" and "Acquired heart disease and pregnancy", section on 'Cardiomyopathy'.)

Reversible increase in LV trabeculations during pregnancy should be distinguished from LVNC. (See "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

MANAGEMENT OF COMPLICATIONS — Data on treatment of LVNC are limited, and there is no specific therapy for LVNC. Medical management varies with the clinical manifestations, LVEF, the presence or absence of arrhythmias, and estimated risk of thromboembolism.

Heart failure — Patients with LVNC with HF should be treated according to standard guidelines. (See "Management of refractory heart failure with reduced ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)

Patients with LVNC who have end-stage HF are candidates for advanced HF therapy or cardiac transplantation evaluation. Successful cardiac transplantation in patients with end-stage HF with LVNC has been reported [16,17]. (See "Heart transplantation in adults: Indications and contraindications".)

Asymptomatic left ventricular systolic dysfunction — Patients with LVNC with asymptomatic LV systolic dysfunction should be treated according to standard guidelines. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)

Thromboembolism — The optimum strategy for managing risk of thromboembolism in patients with LVNC is uncertain given scant data on risk assessment and the efficacy of therapy.

●Patients with LVNC and atrial fibrillation who meet standard criteria for anticoagulation should be anticoagulated according to standard guidelines. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

●Patients with LVNC with a prior cardioembolic event or intracardiac thrombus are treated with anticoagulation, consistent with standard recommendations for cardiogenic embolism. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Cardiogenic embolism'.)

●We suggest anticoagulation in patients with LVNC with LVEF <40 percent and/or atrial fibrillation who do not otherwise have an indication for anticoagulation. Scant data are available to support this approach. Patients with LVNC and atrial fibrillation or depressed LVEF may represent a high-risk group for thromboembolism, similar to HCM. The utility of CHA₂DS₂-VASc score in patients with LVNC and atrial fibrillation has not been established. We suggest anticoagulation in patients with LVNC and atrial fibrillation regardless of CHA₂DS₂-VASc score. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'For symptomatic AF' and "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis", section on 'Thromboembolism'.)

We acknowledge that this approach differs from the general recommendation not to administer anticoagulant therapy to patients with LV systolic dysfunction (with or without HF) in the absence of a specific indication for anticoagulant therapy. We do not see any role for antiplatelet therapy in LVNC. (See "Antithrombotic therapy in patients with heart failure", section on 'Role of antithrombotic therapy'.)

Arrhythmias — For patients with LVNC who survive an episode of sustained ventricular tachycardia or sudden cardiac arrest (SCA), implantable cardioverter-defibrillator (ICD) therapy is warranted for secondary prevention of SCA [9]. The role of ICD therapy in patients with cardiomyopathy for secondary prevention of SCA is discussed further separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

For patients with LVNC with an LVEF ≤35 percent and New York Heart Association (NYHA) class II to III HF, we suggest ICD implantation for primary prevention of SCA [9]. Limited data are available to support this approach (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

An observational study evaluated outcomes in 44 patients with LVNC treated with ICD implantation; 12 were treated for secondary prevention and 32 were treated for primary prevention [18]. After a median of six months, 4 of 12 (33 percent) in the secondary prevention group and 4 of 32 (13 percent) in the primary prevention group presented with appropriate ICD shocks. Inappropriate ICD therapy occurred in 25 percent of the secondary prevention group and 19 percent of the primary prevention group at a median of four months. A study of adults with LVNC or congenital heart disease undergoing ICD implantation reported low rates of periprocedural complications [19].

Since patients with LVNC are at risk for SCA, some have proposed developing an LVNC risk model to determine the likelihood of benefit from an ICD, similar to the HCM Risk-SCD model calculator [20]. One potential component of such a model might be a fragmented QRS complex. In a study of 88 patients with LVNC, the presence of fragmented QRS complex was found to be an independent predictor of arrhythmic events (hazard ratio [HR] 3.850, 95% CI 1.062-9.947) and cardiovascular mortality (HR 2.719, 95% CI 1.494-9.262) [21].

As noted above, we suggest periodic ambulatory ECG (Holter) monitoring in patients with LVNC.

PROGNOSIS — Isolated LVNC is associated with high rates of morbidity and mortality in children and adults. Adverse prognostic factors include severe disease at clinical presentation (eg, worse New York Heart Association [NYHA] functional class), presence of late gadolinium enhancement (LGE) on CMR imaging, and depressed LVEF.

A systematic review included five studies with a total of 241 adults with isolated LVNC with mean 39-month follow-up [22]. The annualized event rate was 4 percent for cardiovascular deaths; 6.2 percent for cardiovascular death, heart transplantation, and appropriate ICD shocks; and 8.6 percent for all cardiovascular events (death, stroke, ICD shocks, and cardiac transplantation). The overall mortality rate was 14 percent during 39 months; nearly one-half of deaths were from SCA. Five percent of patients died from HF.

In a series of 115 patients from one of the centers included in the systematic review (age >14 years, mean age 41), 77 percent were symptomatic at diagnosis, with 43 percent presenting with a cardiovascular complication (HF, systemic embolic event, or sustained ventricular arrhythmia). During a median follow-up of 2.7 years, none of the asymptomatic patients died or underwent heart transplantation compared with 31 percent of symptomatic patients. Cardiovascular complication at presentation (hazard ratio [HR] 20.6) and NYHA class III or greater (HR 8.8) were stronger predictors of cardiovascular death or transplantation than LV dilatation and systolic dysfunction [23].

The prognostic value of LGE detected by CMR and LVEF was demonstrated by a meta-analysis which included four prospective observational studies with a total of 574 patients with LVNC and 677 control patients with similar clinical presentation but without LVNC [24].

●During an average follow-up of 5.2 years, the combined endpoint (cardiac death, sudden cardiac death [SCD], appropriate defibrillator firing, resuscitated cardiac arrest, cardiac transplantation, or assist device implantation, HF hospitalization, ischemic stroke, or other thromboembolic event) was reached in 21 percent of patients with LVNC and 20 percent in patients without LVNC.

●Among patients with LVNC, the combined endpoint occurred in 34 percent of those with LGE and 16 percent of those without LGE (pooled odds ratio [OR] 4.9, 95% CI 1.63-14.6). LGE was also significantly associated with hard cardiac events (cardiac death, SCD, appropriate ICD firing, cardiac arrest, cardiac transplantation, and LV assist device [LVAD] implantation; pooled OR 4.1, 95% CI 1.15-14.5).

●LGE was significantly associated with the combined endpoint and the hard cardiac events in the subgroup of patients with preserved LVEF (>50 percent) as well as in the subgroup of patients with impaired systolic function (LVEF ≤50 percent). Reduced LVEF was significantly associated with hard cardiac events. No hard cardiac events were observed among the 158 patients with LVNC with preserved LVEF and negative LGE.

MACE are more common in patients with LVNC and MYBPC3 or TTN mutations, a history of arrhythmias, nonsarcomere-nonarrhythmia cardiomyopathies, and X-linked genes [25]. Children with LVNC are also at increased risk of MACE including heart failure, arrhythmias and thromboembolic events.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy".)

SUMMARY AND RECOMMENDATIONS

●Genetic testing is recommended in patients with left ventricular noncompaction (LVNC), especially in children and those with a family history of cardiomyopathy.

●Patients with LVNC with heart failure (HF) or asymptomatic LV systolic dysfunction are treated according to standard recommendations for these disorders. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

●Patients with LVNC and atrial fibrillation who meet standard criteria for anticoagulation should be anticoagulated according to standard guidelines. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".)

●We suggest anticoagulation in patients with LVNC with atrial fibrillation or LV ejection fraction (LVEF) <40 percent (Grade 2C).

●For patients with LVNC who survive an episode of sustained ventricular tachycardia or sudden cardiac arrest (SCA), implantable cardioverter-defibrillator (ICD) therapy is warranted for secondary prevention of SCA. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

●For patients with LVNC, an LVEF ≤35 percent, and New York Heart Association (NYHA) class II to III HF; or the combination of LVNC, an LVEF ≤35 percent, and a positive family history for SCA; we suggest ICD therapy for primary prevention of SCA (Grade 2C) (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

●Patients with LVNC who have end-stage HF are candidates for advanced therapies, including cardiac transplantation. (See 'Heart failure' above and "Heart transplantation in adults: Indications and contraindications".)