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Management and prognosis of asymptomatic left ventricular systolic dysfunction

Management and prognosis of asymptomatic left ventricular systolic dysfunction
Literature review current through: May 2024.
This topic last updated: Oct 10, 2023.

INTRODUCTION — Asymptomatic left ventricular systolic dysfunction (ALVSD) is defined as depressed LV systolic function in the absence of heart failure (HF) symptoms, which is called "stage B HF" in the American College of Cardiology/American Heart Association guidelines [1]. (See "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction", section on 'Definition'.)

The management and prognosis of patients with asymptomatic LV systolic dysfunction will be reviewed here.

The evaluation and diagnosis of ALVSD are discussed elsewhere. (See "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction".)

Issues related to the management of patients with HF symptoms (ie, stages C and D) and reduced ejection fraction are presented separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with mildly reduced ejection fraction".)

GENERAL MEASURES

Risk factors for left ventricular dysfunction — Conditions that may contribute to LV dysfunction should be recognized and managed according to standard recommendations [1]. These conditions include hypertension, dyslipidemia, obesity, toxic exposures, and diabetes mellitus. Patients should also be counseled regarding smoking cessation as well as avoidance of cocaine, amphetamines, and heavy alcohol use. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Choice of drug therapy in primary (essential) hypertension".)

Causes of left ventricular dysfunction — We provide appropriate therapy for diseases that cause LV function. At times, provision of such therapies (eg, mitral valve replacement) may alter the approach to therapy. (See 'Factors that influence therapeutic decisions' below.)

The details on the many causes of LV systolic dysfunction are discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Heart failure with reduced ejection fraction'.)

Management of patients with stable ischemic heart disease (including assessment for revascularization and antianginal therapy) and lipid therapy in patients with known cardiovascular disease (including ischemic heart disease) is discussed separately. (See "Chronic coronary syndrome: Overview of care" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Drugs to avoid — Drugs that may worsen ventricular function or exacerbate HF should be avoided in patients with ALVSD. These drugs are reviewed separately. (See "Drugs that should be avoided or used with caution in patients with heart failure".)

Monitoring — Periodic monitoring is indicated to assess for possible worsening of LV function and progression to HF. We recommend echocardiographic assessment when symptoms of HF appear in patients with established ALVSD. In addition, some experts suggest follow-up echocardiographic evaluation in asymptomatic patients to assess the response to treatment. The timing of such monitoring is determined by the stability of left ventricular ejection fraction (LVEF) in the past, the likelihood that a change in LVEF will lead to a change in therapy, and the need to provide prognostic information to the patient.

APPROACH TO INITIAL MEDICAL THERAPY

Factors that influence therapeutic decisions — In general, patients who may benefit from pharmacologic therapy include those with more severe LV dysfunction, evidence of abnormal LV structure and function (eg, LV dilation), causes of ALVSD not amenable to disease-specific therapy, or in whom the effects of therapy are delayed or unclear (eg, alcohol cessation) (algorithm 1). In contrast, therapy may be deferred in favor of prompt clinical follow-up and repeat evaluation of LVEF in patients with mild LV systolic dysfunction (eg, LVEF >40 percent) who have no other signs of abnormal LV structure of function.

Thus, the decision to treat and the exact approach to treatment (eg, timing, choice of agents) are informed by factors that include:

Certainty that symptoms of HF are not present. (See "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction", section on 'Reassess for heart failure symptoms'.)

Specific cause of LV dysfunction (eg, myocardial infarction [MI], valvular, idiopathic). (See "Determining the etiology and severity of heart failure or cardiomyopathy".)

Expectation of reversibility (eg, availability and efficacy of disease-specific treatments [eg, alcohol cessation], correction of causative conditions [eg, sepsis]).

Severity and certainty of abnormal LV structure and function (eg, LVEF value, quality of diagnostic images, presence of ventricular dilation). (See "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction", section on 'Definition'.)

History of myocardial infarction — In patients with ALVSD who had an MI, we suggest combination therapy with one agent from each of the following classes of medications, rather than other combinations of treatment (algorithm 1). Factors that may alter the approach to treatment are noted elsewhere in this topic. (See 'Factors that influence therapeutic decisions' above.)

Combination therapy includes one agent from each of the following groups of agents:

Renin-angiotensin-aldosterone system (RAAS) inhibitor (ie, angiotensin converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], or sacubitril-valsartan).

Beta blocker (ie, carvedilol, metoprolol succinate, bisoprolol).

Mineralocorticoid receptor antagonist (MRA).

Our approach to patients with ALVSD who do not respond to initial therapy is discussed elsewhere in this topic. (See 'Low ejection fraction despite treatment' below.)

Our approach is similar to that in North American professional guidelines, though our certainty of the effectiveness of these agents is lower than suggested by the guidelines [1].

The typical strategy for initiation of this regimen is to start low doses of a RAAS inhibitor and a beta blocker before discharge after MI. We assess for any complications of therapy in the next one to two weeks, and, if kidney function and potassium levels are sufficiently low for initiation of an MRA, we start MRA therapy. It is reasonable to use other strategies (eg, order of therapy) for initiation of therapy, but therapy started in the hospital is more likely to continue in the outpatient setting.

The cautions for use, dosing, and monitoring for these agents are similar to those for patients with HF with reduced ejection fraction (HFrEF), which are described separately:

ACE inhibitors, sacubitril-valsartan, ARB. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Sacubitril-valsartan, ACE inhibitor, or ARB'.)

Beta blockers. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

MRAs. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)

This therapeutic regimen is based upon indirect evidence that includes placebo-controlled clinical trials and trials that included patients with and without HF symptoms. The strongest evidence of efficacy is for ACE inhibitors, while the rationale for use of beta blockers and MRAs are based on trials predominantly composed of patients with HF symptoms. While sodium-glucose co-transporter 2 (SGLT2) inhibitors are appropriate therapy for patients with LV systolic dysfunction and HF symptoms, the role of these agents in asymptomatic patients with ischemic LV systolic dysfunction is unclear. The data include:

ACE inhibitors, sacubitril-valsartan, ARBs – Our approach to the use of RAAS inhibitors in this group of patients is based on trials that included patients with and without HF symptoms. The use of sacubitril-valsartan in this population is based on its efficacy in HFrEF and a class effect.

In a trial (SAVE) that assigned 2231 patients with an LVEF of 40 percent and no overt HF symptoms to placebo or captopril within 3 to 16 days following an MI, there were lower rates of mortality (relative risk [RR] 0.81, 95% CI 0.68-0.97) and progression to HF (RR 0.63, 95% CI 0.5-0.8) [2,3].

Other trials of RAAS inhibitors included many patients with similar types of indirectness to patients with ALVSD:

-In the PARADISE trial that included 5661 patients with AMI who had evidence of LV systolic dysfunction, pulmonary congestion, or both and at least one additional risk factor, patients randomly assigned to sacubitril-valsartan and ramipril had similar rates of death (5.9 versus 6.7 percent) and HF hospitalization (49 versus 51 percent) [4]. Approximately 55 percent of patients had at least Killip Class II symptoms.

-The SOLVD prevention trial consisted of 4228 patients (83 percent had had an MI more than 30 days from entry) with an LVEF ≤35 percent who did not require medical therapy for HF, though approximately 33 percent had New York Heart Association class II HF symptoms [5]. The patients were randomly assigned to enalapril (20 mg once per day) or placebo. At a mean follow-up of approximately three years, enalapril therapy was associated with a reduction in HF hospitalizations (8.7 versus 12.9 percent with placebo) and similar rates of all-cause death (14.8 versus 15.8 percent). In a follow-up analysis, the enalapril group had significant reductions in all-cause mortality (51 versus 56 percent for placebo) and cardiovascular mortality (37 versus 42 percent). No data were available on posttrial drug use [6].

-Other trials with similar designs and findings include the Trandolapril Cardiac Evaluation (TRACE) trial [7,8], the OPTIMAAL trial [9], and the VALIANT trial [10].

Beta blockers – As an acute therapy typically initiated soon after the diagnosis of MI, there is consistent evidence that beta blockers reduce rate of both sudden death and recurrent MI. This evidence is discussed separately. (See "Acute myocardial infarction: Role of beta blocker therapy".)

The long-term efficacy of beta blocker therapy in patients with LV systolic dysfunction was established in trials of patients with HFrEF with or without MI:

In the CAPRICORN trial, almost 2000 patients with an LVEF ≤40 percent after an acute MI (the majority of whom were asymptomatic) were treated with an ACE inhibitor and then randomly assigned to carvedilol (6.25 mg/day initially and then progressively increased during the next four to six weeks to a maximum of 25 mg twice daily) or placebo [11]. After a mean follow-up of 1.3 years, carvedilol reduced the rate of all-cause mortality (12 versus 15 percent; hazard ratio 0.77, 95% CI 0.60-0.98).

In the SAVE trial, 35 percent of patients were treated with a beta blocker at the time of randomization to captopril or placebo. After adjustment for baseline difference, beta blocker therapy was associated with a significant 30 percent reduction in the risk of cardiovascular death at one year (13 versus 22 percent for those not on a beta blocker) and a significant 21 percent decrease in the development of HF (17 versus 23 percent) [12].

Additional evidence from trials of beta blockers in patients with HFrEF is discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

MRAs The rationale for use of MRAs in ALVSD comes from indirect evidence from the EMPHASIS-HF trial, which showed a benefit of eplerenone therapy in patients with MI and LVEF ≤40 percent who had clinical evidence of mild HF. The details of this study are discussed separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)

Nonischemic LV dysfunction — In patients with ALVSD from a nonischemic cause or an unknown cause, we suggest initial treatment with a RAAS inhibitor (ACE inhibitor, ARB, sacubitril-valsartan) and a beta blocker, rather than other regimens or no therapy (algorithm 1). Patient factors (eg, LVEF value, cause of LV dysfunction) that should be used to individualize the approach to management are presented elsewhere in this topic. (See 'Factors that influence therapeutic decisions' above.)

Our approach to patients with ALVSD who do not respond to initial therapy is discussed elsewhere. (See 'Low ejection fraction despite treatment' below.)

This approach is consistent with North American professional guidelines, though the guidelines suggest a higher certainty of treatment efficacy [1].

Our approach is primarily based on indirect evidence from trials that evaluated the efficacy of RAAS inhibitors and beta blockers in patients who have an LVEF ≤40 after MI or that evaluated patients with HFrEF, as well as weaker data from retrospective studies. Patients with nonischemic causes of ALVSD were underrepresented in trials of patients with ALVSD. The role of MRAs and SGLT2 inhibitors as initial therapy in patients with nonischemic ALVSD is not well established; there are no dedicated trials in this population. The data include:

In the REVERT trial of 149 asymptomatic patients with an LVEF <40 percent who were randomly assigned to treatment with either 200 or 50 mg of extended release metoprolol or placebo, an increase in LVEF was observed in both beta blocker groups compared with placebo (6 and 4 versus 0 percent at 12 months) [13]. However, clinical outcomes were not evaluated.

A post hoc analysis of the SOLVD prevention trial provided evidence of clinical benefit from beta blocker therapy [14]. Among the asymptomatic patients treated with enalapril, the 24 percent who also received a beta blocker had a significant independent reduction in the risk of death (RR 0.70, 95% CI 0.52-0.95) and in death or hospitalization for symptomatic HF (RR 0.64, 95% CI 0.49-0.83) compared with those using enalapril alone. The mortality benefit with beta blocker therapy was due to a reduction in arrhythmic and pump failure deaths and was not seen in patients assigned to placebo rather than enalapril.

The evidence on the benefits of these therapies in patients with HFrEF are discussed elsewhere. (See 'History of myocardial infarction' above and "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

MANAGEMENT OF THERAPY

Dose — The target dose of any neurohormonal therapy used to treat ALVSD is similar to the target dose used to treat HF with reduced ejection fraction (HFrEF). (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Management of specific agents'.)

Duration of therapy — For most patients who receive therapy for LV dysfunction, therapy continues indefinitely. However, it is reasonable to discontinue therapy if unmanageable side effects occur. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Duration of therapy'.)

Low ejection fraction despite treatment — Patients who received therapy for ALVSD and any disease-specific therapy but who continue to have reduced LVEF without HF symptoms should undergo an evaluation for residual causes of LV dysfunction and for new HF symptoms. Many such patients are likely to have HF symptoms. In general, patients with persistently reduced LVEF should be managed in a manner similar to patients with HFrEF, as discussed separately (table 1 and algorithm 1). (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

The next steps in therapy are typically guided by a general cardiologist or HF cardiologist who can select an appropriate pharmacologic regimen and reassess for any disease-specific therapies.

This approach is based on our view that diseases causing ALVSD are not distinct from the diseases causing HFrEF, and, as such, it is reasonable to treat patients with ALVSD who do not respond to initial therapy with a regimen appropriate for HFrEF in an attempt to slow or reverse LV dysfunction. However, there are no trials that directly assess the efficacy of combination therapy appropriate for HFrEF in this population.

PREVENTION OF SUDDEN DEATH — Some patients with asymptomatic LV systolic dysfunction are candidates for implantable cardioverter-defibrillator (ICD) implantation for primary prevention of sudden cardiac death. The use of ICDs in this population is described in detail separately. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Use of an ICD'.)

PROGNOSIS — Individuals with ALVSD with reduced LVEF have American College of Cardiology/American Heart Association stage B HF and are at increased risk for clinical (ie, stage C or D) HF and death (figure 1):

In a meta-analysis including 10 studies with a total of 24,206 individuals with ALVSD followed for an average of approximately eight years, the adjusted risk of progression to HF was 4.6 events per 100 person-years for those with ALVSD compared with 1 event per 100 person-years in individuals without any ventricular dysfunction [15]. Based upon data from four studies that reported risk of HF per unit change in LVEF, the combined maximally adjusted relative risk of HF per 1 standard deviation lower LVEF was 1.4.

In the SOLVD prevention trial, individuals with LV dysfunction treated with placebo progressed to symptomatic HF at a rate of 9.7 percent per year, and the three-year mortality rate was 15.8 percent [5]. In the enalapril arm, symptomatic HF developed at a significantly lower rate of 6.7 percent per year, but the mortality rate of 14.8 was not significantly lower than that in the placebo arm.

Among 5004 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), 112 individuals (1.7 percent) with asymptomatic LV systolic dysfunction and no prior history of cardiovascular disease were identified [16]. During nine-year follow-up, these individuals were at increased risk for incident HF (adjusted hazard ratio [HR] 8.69, 95% CI 4.89-15.45), cardiovascular disease (adjusted HR 2.21, 95% CI 1.13-3.73), and mortality (adjusted HR 2, 95% CI 1.13-3.54).

Similarly, asymptomatic individuals with regional wall motion abnormalities are at increased risk of cardiovascular morbidity and mortality as illustrated by an analysis from the Strong Heart Study. During eight-year follow-up in the Strong Heart study, presence of baseline regional wall motion abnormalities was associated with 2.5-fold higher risk of cardiovascular events and 2.6-fold higher risk of cardiovascular death after adjustment for other risk factors [17]. Global wall motion abnormalities were associated with a 2.4-fold higher risk of cardiovascular events and 3.4-fold higher risk of cardiovascular death in similar multivariable models.

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: Arrhythmias in adults" and "Society guideline links: Heart failure in adults".)

SUMMARY AND RECOMMENDATIONS

General measures – The approach to management of asymptomatic left ventricular systolic dysfunction (ALVSD) includes treatment (management of contributing conditions, neurohormonal blockade, and arrhythmia management), avoidance of drugs that may precipitate heart failure (HF), and monitoring for progression. (See 'General measures' above.)

Approach to initial medical therapy

Factors that influence therapy – In general, patients who may benefit from pharmacologic therapy include those with more severe LV dysfunction, evidence of abnormal LV structure and function (eg, LV dilation), causes of ALVSD not amenable to disease-specific therapy, or in whom the effects of therapy are delayed or unclear (eg, alcohol cessation) (algorithm 1). In contrast, therapy may be deferred in favor of prompt clinical follow-up and repeat evaluation of left ventricular ejection fraction (LVEF) in patients with mild LV systolic dysfunction (eg, LVEF >40 percent) who have no other signs of abnormal LV structure of function. (See 'Factors that influence therapeutic decisions' above.)

Patients with HF symptoms should be managed with therapy appropriate for HF with reduced ejection fraction (HFrEF). (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

History of myocardial infarction – In patients who had a myocardial infarction (MI) and evidence of decreased LVEF but no HF symptoms, we suggest combination therapy with one agent from each of the following classes of medications, rather than other combinations of treatment or no treatment (Grade 2C) (algorithm 1) (see 'History of myocardial infarction' above):

-Renin-angiotensin-aldosterone system (RAAS) inhibitor (eg, angiotensin converting enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], or sacubitril-valsartan).

-Beta blocker (ie, carvedilol, metoprolol succinate, bisoprolol).

-Mineralocorticoid receptor antagonist (MRA).

Factors that may alter the approach to treatment are noted elsewhere in this topic. (See 'Factors that influence therapeutic decisions' above.)

Nonischemic LV dysfunction – In patients with ALVSD from a nonischemic cause or an unknown cause, we suggest initial treatment with a RAAS inhibitor (ie, ACE inhibitor, ARB, sacubitril-valsartan) and a beta blocker rather than other regimens of therapy or no therapy (Grade 2C) (algorithm 1). (See 'Nonischemic LV dysfunction' above.)

Factors that may alter the approach to treatment are noted elsewhere in this topic. (See 'Factors that influence therapeutic decisions' above.)

Management of therapy

Dose – The target dose of any neurohormonal therapy used to treat ALVSD is similar to the target dose used to treat HFrEF. (See 'Dose' above.)

Duration of therapy – For most patients who receive therapy for LV dysfunction, therapy continues indefinitely. However, it is reasonable to discontinue therapy if unmanageable side effects occur. (See 'Duration of therapy' above.)

Low ejection fraction despite treatment – Patients should undergo an evaluation for residual causes of LV dysfunction and the presence of symptoms. Patients who received therapy for ALVSD and any disease-specific therapy but who continue to have reduced LVEF without HF symptoms should typically be managed in a manner similar to patients with HFrEF, as discussed separately (table 1 and algorithm 1). (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

Prognosis – Individuals with ALVSD are at increased risk for HF and death (figure 1). (See 'Prognosis' above.)

  1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145:e895.
  2. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992; 327:669.
  3. Rutherford JD, Pfeffer MA, Moyé LA, et al. Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators. Circulation 1994; 90:1731.
  4. Pfeffer MA, Claggett B, Lewis EF, et al. Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction. N Engl J Med 2021; 385:1845.
  5. SOLVD Investigators, Yusuf S, Pitt B, et al. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327:685.
  6. Jong P, Yusuf S, Rousseau MF, et al. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet 2003; 361:1843.
  7. Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995; 333:1670.
  8. Buch P, Rasmussen S, Abildstrom SZ, et al. The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years. Eur Heart J 2005; 26:145.
  9. Dickstein K, Kjekshus J, OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002; 360:752.
  10. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349:1893.
  11. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001; 357:1385.
  12. Vantrimpont P, Rouleau JL, Wun CC, et al. Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol 1997; 29:229.
  13. Colucci WS, Kolias TJ, Adams KF, et al. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial. Circulation 2007; 116:49.
  14. Exner DV, Dries DL, Waclawiw MA, et al. Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1999; 33:916.
  15. Echouffo-Tcheugui JB, Erqou S, Butler J, et al. Assessing the Risk of Progression From Asymptomatic Left Ventricular Dysfunction to Overt Heart Failure: A Systematic Overview and Meta-Analysis. JACC Heart Fail 2016; 4:237.
  16. Yeboah J, Rodriguez CJ, Stacey B, et al. Prognosis of individuals with asymptomatic left ventricular systolic dysfunction in the multi-ethnic study of atherosclerosis (MESA). Circulation 2012; 126:2713.
  17. Cicala S, de Simone G, Roman MJ, et al. Prevalence and prognostic significance of wall-motion abnormalities in adults without clinically recognized cardiovascular disease: the Strong Heart Study. Circulation 2007; 116:143.
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