Identification of High‐Risk Chronic Heart Failure Patients in Clinical Practice: Role of Changes in Left Ventricular Function

Abstract

Background:

Left ventricular (LV) dysfunction and remodeling are key pathophysiological features underlying disease progression in chronic heart failure (CHF).

Hypothesis:

To describe the course of LV dysfunction and identify predictors and prognostic impact of changes in LV volumes and function in stable CHF patients under optimal therapy.

Methods:

There were 318 consecutive CHF outpatients who underwent a repeated echocardiographic evaluation at baseline and at 1 year and subsequently followed‐up for at least 12 months. The end point of the study was all‐cause mortality.

Results:

Mean LV ejection fraction (LVEF) was 33 ± 7% at baseline and 36 ± 9% at follow‐up. Twenty‐four percent of patients had an improvement of LVEF >5 absolute points (group 1); 58% remained stable (group 2), 17% worsened at >5 absolute points (group 3). Age, New York Heart Association class, diuretic dose, renal function, and baseline LVEF were independent predictors of LVEF improvement at 1 year. At the Cox analysis, patients in group 3 had a 4‐fold higher risk of death when compared with group 1 (hazard ratio: 3.99, 95% confidence interval: 1.6‐9.9, P = 0.002), independently of age, etiology, and symptoms severity.

Conclusions:

In stable CHF outpatients, LV function improves in 24% of cases; a modest decrease in LV systolic function is associated with a significantly higher risk of all‐cause mortality, independent of other markers of disease severity. Clin. Cardiol. 2012 doi: 10.1002/clc.22024

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Left ventricular (LV) remodeling represents the underlying mechanism of cardiac dysfunction in approximately half of all chronic heart failure (CHF) cases,1 independent of the primary cause of damage to the heart.2 It is defined as a multifaceted process provoking those changes in shape, dimensions, and function of the heart, which start before the clinical manifestations of the syndrome and may ultimately lead to worsening of symptoms and refractory end‐stage disease. In absence of specific treatment, the process appears to advance indefinitely.3., 4., 5., 6.

Therapeutic interventions that interfere with the natural history of the disease and improve outcome exert a reverse‐remodeling effect.7., 8., 9., 10. Nevertheless, the current literature lacks information regarding the course of the disease in patients in whom all available therapeutic strategies have been used. In particular, it is not clear whether inexorable decline or stabilization of LV function has to be expected over time, and how this would affect outcome. We aimed to describe the course of LV dysfunction and volumes, identify predictors and prognostic impact of changes in LV volumes, and identify function in stable CHF outpatients optimally treated.

Methods

We prospectively studied 318 consecutive CHF outpatients followed by the Heart Failure Outpatient Clinic of our Institution, with the following inclusion criteria: CHF due to dilated cardiomyopathy of any etiology, stable clinical conditions and no hospital admissions over the last month before enrolment, optimal medical and device therapy since at least 6 months, and a good echocardiographic window. The study was approved by local ethics committee, and patients provided written informed consent. Investigation was in accordance with the Declaration of Helsinki.

Complete 2‐dimensional and Doppler color flow examinations were performed at baseline and at 1‐year follow‐up with an Acuson 512 XP machine (Siemens Medical Solutions USA, Inc., Malvern, PA) and a 3.5 MHz transducer by a single operator. Left ventricular end‐diastolic (LVEDV), end‐systolic volume (LVESV), and LV ejection fraction (LVEF) were determined by Sympson method11 and have been adjusted by body surface area. LV diastolic function was investigated by analyzing the transmitral flow pattern with measure of the E wave peak velocity (E v), the E wave deceleration time (DTE), and the E/A ratio pattern.12

Patients were followed‐up for at least 1 year after the 2nd echocardiographic examination. The primary end point of the study was all‐cause mortality; the secondary end point of the study was cardiac death. Patients who underwent heart transplantation were censored as alive at time of transplantation.

Statistical Analysis

Data are expressed as mean ± standard deviation or number (percentage), as appropriate. Student t test for unpaired data or χ ² test were used to assess differences between groups. Changes of LVEF and volumes were calculated as absolute difference between 1‐year follow‐up and baseline data. Patients were then stratified in group 1 (improvement of LVEF of >5 absolute points), group 2 (patients who showed changes of EF ±5 absolute points), group 3 (worsening of LVEF of >5 absolute points).

Univariate or multivariate logistic or regression analyses were performed to assess the relation between changes in LV function and variables (significance level for entering the analysis model ≤0.05). Survival analysis was performed by means of univariate and multivariate Cox model and Kaplan‐Meier survival curves. P< 0.05 was considered statistically significant (Statview 4.5; Abacus Concepts Inc., Piscataway, NJ).

Results

Baseline characteristics of study population are outlined in Table 1. Most patients were male (87%), 61% of cases of dilated cardiomyopathy were of ischemic origin. Most patients were on angiotensin‐converting enzyme inhibitors or angiotensin II‐receptor blockers (90%), β‐blockers (77%), and diuretics (90%). Mean LVEF was 33 ± 7%. One hundred nineteen patients (37%) had an implantable cardioverter‐defibrillator and 67 (21%) a biventricular pacemaker.

Table 1.

Baseline Clinical Characteristics of the Study Population

Variable	Value
Male gender (%)	276 (87)
Age (y)	61.6 ± 9.7
Etiology
Ischemic	193 (61)
Idiopathic	111 (35)
Valvular	9 (3)
Alcoholic	2 (0.6)
Chemotherapy‐related	3 (0.9)
NYHA class
I	46 (15)
II	175 (55)
III	90 (28)
IV	7 (2)
Sinus rhythm	252 (79)
Atrial fibrillation	66 (21)
Left bundle branch block	63 (20)
Right bundle branch block	20 (6)
SBP (mm Hg)	120 ± 13
DBP (mm Hg)	75 ± 9
BMI (kg/m2)	26.2 ± 3.7
Diabetes mellitus	67 (21)
Creatinine (µmol/L)	105 ± 32
Medical therapy
Diuretics	273 (90)
ACE‐inhibitors/ARBs	275 (90)
β‐Blockers	227 (77)
Aldosterone antagonist	82 (24)
Statin	238 (69)
LVEF (%)	33 ± 7
LVEDV (mL/m2)	148 ± 54
LVESV (mL/m2)	101 ± 48
E wave velocity (m/sec)	0.70 ± 0.28
DTE (msec)	155 ± 46
E/A ratio	1.5 ± 1.1
RMFP	32 (10)

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin‐receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; DTE, E wave deceleration time; LVEDV, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end‐systolic volume; NYHA, New York Heart Association; RMFP, restrictive mitral filling pattern; SBP, systolic blood pressure. Data are presented as mean ± standard deviation or number (%) as appropriate.

Mean follow‐up time was 64.1 ± 25.4 months (range, 4.8–78.5 months). During this period, 70 deaths (22%) occurred (end‐stage heart failure, 11%; sudden cardiac death, 5%, noncardiac deaths, 2.8%; unknown reasons 3.1%). There were 2.8% nonurgent transplantations.

Mean LVEF was 36 ± 9% at follow‐up. Twenty‐five percent of patients had an improvement of LVEF >5% (group 1), 58% remained stable (group 2), and 17% worsened >5% (group 3). Twenty‐five patients (8%) improved their systolic function up to a LVEF >50%. Univariate and multivariate predictors of LVEF variations are reported in Table 2.

Table 2.

Factors Predicting LVEF Improvement (Absolute Difference Between Follow‐up and Baseline) During the First Year of Follow‐up (Univariate and Multivariate Analyses)

Variable	Univariate Analysis		Multivariate Analysis
	r	P	P
Age (y)	−0.13	0.018	0.07
NYHA class	−0.15	0.01	0.04
Frusemide dose (mg)	−0.12	0.03	NS
Nonischemic etiology	—	0.002	0.006
S‐creatinine (µmol/L)	−0.14	0.01	NS
QRS (msec)	—	NS	—
S‐Na+ (mEq/L)	—	NS	—
Biventricular PM	—	NS	—
LVEF (%)	−0.22	0.0001	≤0.0001
LVEDV (mL/m2)	—	NS	—
LVESV (mL/m2)	—	NS	—
DTE (msec)	—	NS	—
E/A ratio	0.14	0.08	—
RMFP	—	NS	—

Abbreviations: DTE, E wave deceleration time; LVEDV, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end‐systolic volume; NYHA, New York Heart Association; NS, not significant; PM, pacemaker; RMFP, restrictive mitral filling pattern.

P < 0.05 was considered statistically significant. Only significant univariate predictors were included in the multivariate model.

At the Cox model (Table 3), patients in group 3 had a 4‐times higher risk of all‐cause mortality when compared with group 1, whereas there was no statistically significant difference between group 2 and 3. Similarly, group 3 patients had a 3‐fold higher risk of cardiac death when compared with group 1. Kaplan‐Meier curves illustrate the survival rates among groups (P < 0.0001; Figure 1). Group 1 had a 100%, a 98%, and a 91% survival rate at 12, 24, and 60 months, respectively, as opposed to 98%, 93%, and 86% survival rate for group 2 and a 100%, 91%, and 65% survival rate for group 3, respectively. Those patients who improved their systolic function up to normalization (LVEF >50%) had a 100% 60‐month survival rate.

Table 3.

Predictors of All‐Cause Mortality in the Study Population (Cox Univariate and Multivariate Analyses)

Variable	Univariate Analysis		Multivariate Analysis
	HR (95% CI)	P	HR (95% CI)	P
Age (y)	1.06 (1.03‐1.09)	0.001	1.05 (1‐02‐1.08)	0.02
Ischemic etiology	1.81 (1.08‐3.04)	0.02	—	NS
NYHA functional class	2.05 (1.44‐2.92)	<0.0001	1.67 (1.001‐2.79)	0.04
Diuretic dose (mg)	1.01 (1.01‐1.02)	<0.0001	1.006 (1.002‐1.009)	0.013
QRS (msec)	1.01 (1.01‐1.02)	<0.0001	—	NS
S‐creatinine (µmol/L)	1.01 (1.01‐1.02)	<0.0001	1.01 (1.002‐1.02)	0.02
S‐Na+ (mEq/L)	0.93 (0.86‐0.99)	0.04	—	NS
LVEF (%)	0.92 (0.89‐0.95)	<0.0001	0.84 (0.77‐0.94)	0.0009
EDV (mL/m2)	1.003 (1.001‐1.005)	<0.0001	—	NS
ESV (mL/m2)	1.004 (1.002‐1.006)	<0.0001	—	NS
DTE (msec)	0.99 (0.98‐0.99)	0.002	0.98 (0.96‐0.99)	0.03
ΔLVEF (%)	—	NS	—	—
ΔLVEF group 3a	4.2 (2.01‐8.79)	0.0001	3.99 (1.61‐9.89)	0.002
ΔLVEF group 2a	—	NS	—	—

Abbreviations: CI, confidence interval; DTE, E wave deceleration time; EDV, end‐diastolic volume; ESV, end‐systolic volume; HR, hazard ratio; LVEF, left ventricular ejection fraction; NS, not significant; NYHA, New York Heart Association.

P < 0.05 was considered statistically significant. Only significant univariate predictors were included in the multivariate model.

^aComparison with ΔLVEF group 1.

Figure 1.

Kaplan‐Meier survival curves of the study population divided according to left ventricular ejection fraction (LVEF) changes at 12‐month follow‐up.

LVEDV improved in 22% of patients (>10% reduction as compared with baseline), worsened in 45% of patients (>10% increase as compared with baseline), and did not vary in 33% cases; 28% patients had an improvement, 28% worsened, and 44% remained stable in regard to their LVESV. The only predictors of LVESV and LVEDV variations were systolic blood pressure (P = 0.045, r = −0.18 and P = 0.028, r = −0.22, respectively), baseline EDV (P = 0.004, r = 0.29 and P = 0.004, r = 0.22, respectively), and baseline ESV (P = 0.006, r = 0.23 and P = 0.008, r = 0.20, respectively) at the univariate analysis. At the multivariate analysis, only baseline LVEDV and LVESV resulted in independent predictors of LVEDV variations, whereas the only independent predictor of LVESV variations was systolic blood pressure. LVEDV and LVESV variations did not prove to impact patients' prognosis at the survival analysis (P = 0.31 and P = 0.48, respectively, in the Cox model).

Discussion

In the present study we described the course of LV systolic function and volumes in a large population of stable CHF under optimal treatment, and found that at 1 year about half of the patients remained stable, whereas 24% had an improvement and 17% worsened their LVEF >5 points, with a similar trend for LV volumes. Variations in LVEF, but not in volumes, had a strong impact on survival rate, with a 4‐fold increase in mortality in patients with worsening LVEF as compared with those who improved their LVEF.

Remodeling and cardiac dysfunction are a multilevel process proceeding from a genetic and molecular up to a cellular and interstitial level.13., 14., 15., 16. Medical treatment, historically directed to modulation of neurohormonal systems, aims to interfere with this process. Some patients improve their systolic function and volumes, an event named reverse remodeling; however, it is a common clinical observation that the patient's response to standard treatment is not fully predictable. In many cases, it is likely that CHF treatment starts long after the onset of LV dysfunction, because remodeling precedes clinical signs and symptoms.

Drugs that interfere with the renin‐angiotensin‐aldosterone system (RAAS) and sympathetic nervous systems can get to the core of the remodeling process whether and when it is mainly dependent on the vicious cycles of these hormones. It could be the case of the 8% of patients reaching an EF >50% in our study. However, when the process is too advanced, or if it depends on mechanisms other than those we know, medical therapy fails to promote reverse remodeling. Our study population was homogenous in terms of therapeutic background. Therefore, we believe that LVEF and volume variations might also be partly attributable to an individual variability in response to medical therapy.17

RAAS antagonists9., 18., 19., 20., 21. and β‐blockers22., 23., 24., 25., 26., 27. improve symptoms and prolong survival, and these effects parallel the improvements in LV volumes and systolic function.28 We studied this association, dividing our population into subgroups according to variations in LVEF to assess their impact on patients' survival. Interestingly, even a clinically nondetectable 5‐point reduction in LVEF value was associated with a 4‐fold higher risk of death as compared with patients with an improvement of their LVEF of similar extent, independently of other strong prognostic variables.

Conclusion

In CHF patients, small LVEF variations strongly predict prognosis. These results may strengthen the role of echocardiography in the follow‐up of otherwise stable CHF patients, and provide an useful tool to identify high‐risk patients who may benefit from intensified follow‐up and treatment.