Left Atrial Distensibility Guiding Management in Advanced Chronic Heart Failure
Left Atrial Distensibility Guiding Management in Advanced Chronic Heart Failure
Background and Purpose- According to our prior studies, left atrial (LA) distensibility was
 associated significantly with left ventricular filling pressure in patients with acute
 myocardial infarction (AMI), chronic stable angina, and severe mitral regurgitation. LA
 distensibility can be used as noninvasive Swan-Ganz catheter. Additionally, it could predict
 in-hospital mortality in AMI patients. In the current study, left atrial distensibility
 guiding management in advanced chronic heart failure will be performed to assess whether
 those management could influence long-term prognosis including mortality rate,
 rehospitalization rate and the duration of rehospitalization.

 Materials and Methods- Advanced chronic heart failure (HF) is defined as left ventricular
 ejection fraction less than 35%, creatinine less than 2 mg/dL, and CHF NY functional class
 III-IV for more than 3 months. Enrolled patients should be admitted to hospital due to heart
 failure requiring adjustment of inotropic agents or diuretics within recent 6 months. Three
 hundred HF cases will be recruited - 100 with sinus rhythm, and 100 with atrial fibrillation
 served as LA distensibility guided treatment group (guide group) and another 100 patients,
 either sinus rhythm or atrial fibrillation, served as control group. The management of guide
 group will be adjusted by LA distensibility, including the dose of inotropic agents,
 diuretics, beta-blocker, ACEI, and AIIB. Initially, the guide group will be followed 1 time
 per 2 week at first 3 months, then 1 time per month later. The control group will be treated
 by conventional management and traditional echocardiography can be performed as in-charge
 doctor request. The necessity of hospitalization for heart failure will be adjusted by 2
 cardiovascular specialists and all patients admitted for heart failure will be managed by the
 same one cardiovascular specialist (Shih-Hung Hsiao). The total duration of follow-up will be
 2 years. For life-threatening heart failure, intravenous nitroprusside drip under continuous
 A-line monitor, percutaneous coronary intervention, Swan-Ganz catheter insertion,
 intra-aortic balloon pump, and ECMO can be done according to the order of in-charge doctor.
 The primary end-point will be all-cause mortality. The second end-points will be heart
 failure with hospitalization and the duration of each hospitalization. Additionally, the
 ratios of medication changes in 2-year follow-up, including diuretics, inotropic agents, beta
 blockers, ACEI, and AIIB, will be assessed. Analysis will also be performed to estimate the
 trends of heart function (either systolic or diastolic) and renal function during 2-year
 follow-up according to whether guiding by LA distensibility is done or not.
Background: The use of E/Em (mitral early-diastolic velocity divided by mitral
 early-diastolic annular velocity) assessing left ventricular filling pressure has some innate
 defect since it was born to assess the regional function of myocardium. It is rational to
 infer that ischemic heart disease with regional wall motion defect will affect the
 measurement of tissue Doppler and, thereupon, influence the accuracy of using regional
 parameters to estimate global function. Conduction disturbance with bundle branch block is
 another significant confounder, since it truly influences the data of regional peak Em.
 Therefore, it is necessary to develop or design a new global parameter to overcome the
 handicap of tissue Doppler. In our recent studies (1, 2), there are significant logarithmic
 relationships between LV filling pressure and LA distensibility in patients with acute
 myocardial infarction received primary percutaneous coronary intervention and in patients
 with severe mitral regurgitation. In patient received coronary intervention for chronic
 angina pectoris, the relationship is also similar (submitted to J Am Soc Echocardiogr. under
 major revision). In our recent ongoing study, LA distensibility is applied to low-risk
 general population for assessing the risk of stroke, cardiovascular event, mortality and the
 presence of atrial fibrillation. This time, the investigators try to use this parameter to
 monitor patients with advanced chronic heart failure (high-risk group) and to adjust
 patient's management and treatment.

 Introduction LA volume provides the significantly prognostic information in the general
 population and patients with heart disease, including acute myocardial infarction (3), left
 ventricular dysfunction (4, 5), mitral regurgitation (6), cardiomyopathy (7, 8) and atrial
 fibrillation (9). Large LA volume, which represents chronic diastolic dysfunction, is
 associated with poor outcome, regardless of systolic function (10). Thereby, LA volume
 provides a long-term view of whether or not the patient has the disease of diastolic
 dysfunction, regardless of whatever loading conditions are present at the time of the
 examination, as the hemoglobin A1C in diabetes mellitus (10). Until recently, the relation
 between LA volume and LV filling pressure has been confirmed directly by simultaneous
 echocardiography-catheterization, which those studies were conduced by our team (1, 2). LA
 distensibility is associated logarithmically with left ventricular filling pressure in
 patients with chronic stable angina, acute myocardial infarction, or severe mitral
 regurgitation. It can be treated as non-invasive Swan-Ganz catheter, which isn't likely to
 affect by the tissue Doppler confounders of regional wall motion defect and bundle branch
 block. Since the relationship between LA distensibility and left ventricular filling pressure
 is logarithmic, LA distensibility would be relatively insensitive in the low-pressure end.
 Therefore, the investigators conduct an investigation that assesses the risk stratification
 of cardiovascular risk by LA distensibility in low-risk general population (potential low
 left ventricular filling pressure) from 2009. This time, LA distensibility will be used to
 guide the treatment of advanced chronic heart failure.

 Methods Study population: Advanced chronic heart failure (HF) will be defined as left
 ventricular ejection fraction less than 35%, creatinine less than 2 mg/dL, and CHF NY
 functional class III-IV for more than 3 months. Enrolled patients should be admitted to
 hospital due to heart failure requiring adjustment of inotropic agents or diuretics within
 recent 6 months. Three hundred HF cases will be recruited - 100 with sinus rhythm, and 100
 with atrial fibrillation served as LA distensibility guided treatment group (guide group) and
 another 100 patients, either sinus rhythm or atrial fibrillation, served as control group.
 The management of guide group will be adjusted by LA distensibility, including the
 adjustments of inotropic agents, diuretics, beta-blocker, ACEI, and AIIB. The control group
 will be treated by conventional management and traditional echocardiography can be performed
 as in-charge doctor request. Renal function will be checked 1 time per 3 months. All patients
 will give written informed consent to participate in the study, and the study will send to
 the institutional review board for approval.

 Conventional echocardiographic and myocardial tissue Doppler measurement: Echocardiography
 will be performed in each patient initially. LV ejection fraction is calculated using
 Simpson's method for biplane images. Mitral inflow is assessed by pulsed-wave Doppler
 echocardiography form the apical 4-chamber view. From the mitral inflow profile, the E-wave
 velocity, A-wave velocity, and E-deceleration time are measured. Pulsed-wave tissue Doppler
 imaging (TDI) is performed using spectral pulsed Doppler signal filters, by adjusting the
 Nyquist limit to 15 - 20 cm/s and using the minimum optimal gain. In the apical 4-chamber
 view, a 3-mm, a pulsed-wave Doppler sample volume is placed at the level of the mitral
 annulus over the septal border. Pulsed-wave TDI results are characterized by a myocardial
 systolic wave (Sm) and 2 diastolic waves: early (Em) and atrial contraction (Am). The
 pulsed-wave TDI tracing is recorded over 5 cardiac cycles at a sweep speed of 100 mm/s and is
 used for offline calculations.

 Measurements of LA volume: All LA volume measurements will be calculated from apical 4- and
 2-chamber views using the biplane area-length method (11). The LA volumes are measured at 3
 points: 1) immediately before the mitral valve opening (maximal LA volume or Volmax); 2) at
 onset of the P-wave on electrocardiography (pre-atrial contraction volume or Volp); and 3) at
 mitral valve closure (minimal LA volume or Volmin). The LA distensibility was calculated as
 (Volmax - Volmin) / Volmin. The LA ejection fraction is calculated as (Volp - Volmin) / Volp.
 In all patients, LA volumes are indexed to body surface area (BSA) (12). For patients with
 atrial fibrillation, the average of 5 LA distensibilities will be used for clinical
 assessment.

 Study Design: This study is a prospective, observational, and open label investigation. The
 guide group will be followed 1 time per 2 week at first 3 months, then 1 time per month
 later, and then 1 time per 3 months. Each time, the guide group should receive
 echocardiography, including the measurement of LA distensibility. LA distensibility-guided
 therapy is enabled in 2 ways. Prescriptions should be adjusted according to overall left
 ventricular filling pressure estimated by LA distensibility. The specified treatments after
 adjustment by the current LA distensibility are also allowed. Investigators individually
 adjust medications for each patient according to the ranges of LA distensibility. The
 specified therapy is based on 5 LA distensibility ranges (very low, low, optimal, high, and
 very high). Each range is associated with a prescription for medication dosing, sodium and
 fluid intake, or activity level. Although there are no specific prescribing rules ad dynamic
 prescribing is at the discretion of the investigators, the general aim is to reduce or
 eliminate diuretic doses for high or very high LA distensibility and increase diuretic or
 vasodilator doses for low or very low LA distensibility. The necessity of hospitalization for
 heart failure will be adjusted by 2 cardiovascular specialists and all patients admitted for
 heart failure will be managed by the same one cardiovascular specialist. The total duration
 of follow-up will be 2 years. Patients will be encouraged to take additional visit if they
 have worsening symptoms. For life-threatening heart failure, intravenous nitroprusside drip
 under continuous A-line monitor, percutaneous coronary intervention, Swan-Ganz catheter
 insertion, intra-aortic balloon pump, and ECMO can be done according to the order of
 in-charge doctor. The primary end-point will be all-cause mortality. The second end-points
 will be heart failure with hospitalization and the duration of each hospitalization.
 Additionally, the ratios of medication changes in 2-year follow-up, including diuretics,
 inotropic agents, beta blockers, ACEI, and AIIB, will be assessed. Analysis will also be
 performed to estimate the trends of heart function (either systolic or diastolic) and renal
 function during 2-year follow-up according to whether guiding by LA distensibility is done or
 not.

 Interobserver variability: In the first 50 enrolled cases, Volmax, Volmin, and Volp will be
 measured by 2 independent observers. Interobserver variability is calculated as the
 difference between the values obtained by the 2 observers divided by the mean. Interobserver
 difference and variability of Volmax, Volmin, and Volp will be assessed.

 Statistical analysis: The SPSS software (version 12) will be used for all statistical
 analyses. All continuous variables are presented as means ± standard deviation. Analysis of
 variance and post hoc test (Scheffe F-test) for unpaired data are used to evaluate the
 significance of differences between groups. A p vale of < 0.05 is considered statistically
 significant. Comparison of clinical characteristics is performed by chi-square analysis for
 categorical variables. Bivariate analysis, simple correlation and linear regression are used
 as appropriate. Target ACEI, AIIB, and beta blocker doses are defined as > 50% of maximal
 American Heart Association/American College of Cardiology heart failure guideline doses. LA
 distensibility control will be empirically defined if the frequency of LA distensibility <
 90% (according to the logarithmic regression curve in acute myocardial infarction patients,
 LA distensibility < 90% indicated left ventricular filling pressure more than 15 mmHg in our
 prior study) is less than 10% for 6 consecutive months. ROC curve analysis is performed to
 assess the sensitivity and specificity of the cut-off points of LA distensibility when
 predicting hospitalization for heart failure and the duration of hospital stay. Kaplan-Meier
 curve will be performed to assess the cumulative event-free rate according to subgroup
 analysis (guide group with sinus rhythm, guide group with atrial fibrillation and control
 group). To evaluate the effect of covariates on mortality and heart failure with
 hospitalization, relative risk and 95% confidence intervals will be calculated as hazard
 ratios derived from the Cox proportional-hazards model.

 Solutions to the Anticipated Difficulty The problem is to unify echocardiographic measurement
 of left atrial border in sonographers participating in this study. Therefore, the
 investigators will perform those measurement in 50 consecutive patients scheduled for routine
 echocardiography and discuss all cases to reduce the technique's error of measurement.

 Anticipated results:

 1. LA distensibility is useful for guiding the management of advanced chronic heart
 failure.

 2. The treatment adjusted by LA distensibility provides more advanced information for
 clinical physician. Therefore, it potentially influences patient's outcome. The
 hypothesis will be confirmed by comparison of the primary and second end-points between
 treatment group and control group.

 3. Although patient with sinus rhythm will be better to assess LA distensibility, the
 average of 5 LA distensibilities in patients with atrial fibrillation is possibly as
 useful as in patients with sinus rhythm. Subgroup analysis of treatment group according
 to whether sinus rhythm or atrial fibrillation will be done to assess the feasibility of
 LA distensibility.
Inclusion Criteria:

 -  Advanced chronic heart failure (HF) will be defined as left ventricular ejection
 fraction less than 35%, creatinine less than 2 mg/dL, and CHF NY functional class
 III-IV for more than 3 months. Enrolled patients should be admitted to hospital due to
 heart failure requiring adjustment of inotropic agents or diuretics within recent 6
 months.

 Exclusion Criteria:

 1. presence of mitral stenosis or prosthetic mitral valve

 2. any abnormality of atrial septum (e.g., atrial septal defect or aneurysm)

 3. inadequate image quality

 4. lack of informed consent