Cardiovasc Toxicol DOI 10.1007/s12012-014-9284-9
ORIGINAL RESEARCH
Left Atrial Function by Speckle-Tracking Echocardiography in Chronic Asymptomatic Alcoholic Patients Gonenc Kocabay • Can Yucel Karabay • Arzu Kalaycı • Vecih Oduncu • Taylan Akgun • Ahmet Guler • Alev Kılıcgedik • Sedat Kalkan • Akin I˙zgi • Cevat Kırma
Ó Springer Science+Business Media New York 2014
Abstract Although the effects of chronic alcoholism on left ventricular (LV) systolic function are well established, diastolic impairment has been evaluated partially. In addition, there are scarce data available about the relation of LV diastolic function to either or both duration and quantity of drinking among alcoholics. The aim of the study was to evaluate the left atrial (LA) function in chronic asymptomatic alcoholic patients by using two-dimensional speckle-tracking echocardiography (2D-STE). We enrolled 30 healthy subjects (age 34.8 ± 5.8 years) and 75 asymptomatic male alcoholics (age 39.8 ± 6.5 years) divided into two groups, according to total lifetime dose of ethanol: group I,\15 kg/kg and group II, C15 kg/kg. In the 2D-STE analysis of the LA, strain during ventricular systole (LARes), during late diastole (LA-Pump) and strain rate during ventricular contraction (LA-SRs), during passive ventricular filling (LA-SRe), during active atrial contraction (LASRa) were obtained. Deceleration time was longer, E/A and Vp were smaller, and E/Em was higher in alcoholics. Although parameters of diastolic dysfunction were comparable in alcoholic groups, LA-Res and LA-Pump were found significantly different among the alcoholics. However, there were no differences in LA-SRs and LA-SRe between the controls and alcoholic groups. LA function is reduced in chronic alcohol abuse, and heavy alcohol consumption may play an important role in LA function impairment.
G. Kocabay (&) C. Y. Karabay A. Kalaycı V. Oduncu T. Akgun A. Guler A. Kılıcgedik S. Kalkan A. ˙Izgi C. Kırma Cardiology Department, Kartal Kosuyolu Heart and Research Hospital, Istanbul, Turkey e-mail: [email protected]
Keywords Left atrial function LV diastolic dysfunction Speckle-tracking echocardiography Chronic asymptomatic alcoholic patients
Introduction Chronic excessive alcohol consumption is a risk factor for developing dilated cardiomyopathy, independently of coronary atherosclerosis and hypertension [1–3]. The subclinical changes of left ventricular (LV) function in noncardiac alcoholics are frequently diastolic rather than systolic abnormality [4]. However, there are scarce data available about the relation of LV diastolic function to either or both duration and quantity of drinking among alcoholics. Studies investigating LV diastolic dysfunction have yielded conflicting results. While some studies found the normal LV filling [3–6], some of them reported impaired LV filling [7–11]. Possible reasons for these discrepancies may be due to the different methods used to assess diastolic function. Studies investigating diastolic function in alcoholics used only transmitral velocity (E/A ratio and deceleration time). Since these parameters are dependent on rate, blood pressure and load (volume), the results may be not diagnostic of diastolic dysfunction. Two-dimensional speckle-tracking echocardiography (2D-STE) is a novel non-Doppler-based method for the angle independent and accurate quantification of myocardial deformation. It has the advantage of being angle independent and to be relatively load-independent indices [12, 13]. With the advent of 2D-STE, we are able to detect early left atrial (LA) dysfunction even before structural changes occur. LA abnormalities are associated with abnormal diastolic dysfunction of the LV. 2D-STE provides the quantification of longitudinal myocardial LA
123
Cardiovasc Toxicol
deformation dynamics, which was recently proposed as an alternative approach for the LV filling pressure estimation [13]. Hence, the aim of the present study was to investigate LA function in chronic alcoholic patients using a combination of 2D-STE and conventional echocardiography, i.e., Doppler-derived indexes and LA volume.
Methods Study Population Between 2010 and 2011, we selected 90 alcoholic male patients who were admitted to the outpatient alcoholism unit for assistance in terminating their dependence on alcohol. The study protocol was approved by the Institutional Review Board of the Hospital, and each subject gave informed written consent to participate. Inclusion criteria were as follows: (1) positive diagnostic criteria for alcohol abuse established by the American Psychiatric Association [14], (2) daily ethanol consumption C90 g and C4 days/week, (3) drinking history C5 years, (4) normal sinus rhythm. Exclusion criteria were as follows: (1) impairment of LV systolic function (ejection fraction, EF \50 %) by using echocardiographic evaluation, (2) patients with previous history of coronary artery disease (CAD, defined as any degree of CAD on previous angiogram or history of myocardial infarction or angina), (3) patients with chronic liver disease or renal dysfunction, (4) history of palpitation or any documented rhythm abnormalities, i.e., supraventricular arrhythmia, on 24-h Holter examination. Of these, five patients with inadequate echocardiographic images, four patients with paroxysmal atrial tachycardia on 24-h Holter examination and three patients with conflicting amount of ethanol intake were excluded from the study. In addition, three patients with positive clinical diagnosis of the liver damage were excluded. For this diagnosis, besides laboratory measurements, the presence of three or more of the following physical findings was used: tender hepatomegaly, palmar erythema, spider angiomata, gynecomastia, and cases having cirrhosis, splenomegaly, ascites and evidence of collaterals on the abdomen were examined. A total of 75 consecutive asymptomatic male alcoholics (age 39.8 ± 6.5 years, age ranged 31–55 years) were enrolled in this study. All patients with their families and friends were questioned by experienced psychiatrists about the total duration of heavy alcohol drinking, and the type and amount of drinks consumed per day. Daily ethanol consumption was obtained by converting the type and amount of alcoholic beverages to grams of absolute ethanol. Alcohol consumption was expressed in grams per day. In order to
123
calculate the total dose of ethanol consumed in their lifetime (total lifetime dose of ethanol, TLDE), this was expressed in kg of ethanol/kg of body weight and was estimated by first multiplying the daily consumption of ethanol by the number of days of the periods of exposure to alcohol and then dividing the product by the body weight of the patient when first admitted. Since TLDE was reported to be a good predictor of LV function in alcoholic patients [8, 16], in advance of data collection, we decided to classify alcoholic patients into two groups according to the TLDE values: group I (TLDE \15 kg ethanol/kg body weight) and group II (TLDE C15 kg ethanol/kg body weight). Because there is no cutoff value for TLDE or other markers such as, duration of drinking and daily alcohol consumption, in this article, we calculated the cutoff level for TLDE as presuming that someone (male gender) is 80–85 kg and drinking more than 17 years (average of 15 and 20 years, coming from previous studies). After the mathematical calculation described above, we found ‘‘15’’ as a cutoff level. Current smokers (more than ten number of cigarettes consumed daily) were recorded. Thirty healthy male controls (age 34.8 ± 5.8 years; controls vs. group I, p = NS; controls vs. group II, p \ 0.001) without drinking histories were evaluated as the control group. None of them had a history of hypertension, diabetes mellitus, dyslipidemia nor any history, signs or symptoms of cardiovascular diseases. Clinical and Laboratory Evaluations A complete physical examination was performed to all subjects. Anthropometric assessments of height and weight were measured, and body mass index (BMI, kg/m2) and body surface area (BSA, m2) were calculated. Blood pressures were measured after 10 min of rest in a quite room. Venous blood samples were taken in the morning after a 12-h fasting. Complete blood counts and biochemical parameters, such as serum glucose, creatinine, total cholesterol and triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were assessed. A 12-lead standard resting electrocardiogram and exercise treadmill stress testing were performed in all patients according to the modified Bruce protocol to exclude the presence of silent myocardial ischemia or significant disturbances of sinus rhythm. None of them had any abnormal test results. Conventional, Pulsed Doppler and Tissue Doppler Echocardiography All echocardiographic measurements were taken by using a commercially available ultrasound system (GE-Vivid 7
Cardiovasc Toxicol
system, Horten, Norway) with a 3.5-MHz transducer. All data were transferred to a workstation for further offline analysis (EchoPAc, GE, Horten, Norway). All measurements and evaluation were taken according to the guidelines of American Society of Echocardiography [17]. The LV end-diastolic diameter (EDD), end-systolic diameter (ESD), end-diastolic thickness of ventricular septum (IVS) and end-diastolic thickness of LV posterior wall (PWT) were measured by M-Mode echocardiography. Using these parameters, we calculated LV mass (g) by the Devereux formula [18]. LV mass index was then determined by dividing the LV mass measurement by the BSA (g/m2). LV-EF was calculated by using Simpson’s method. The LA volume was measured by using the biplane arealength method [19]. The indexed volume of LA (LAVI) was calculated as LA volume/BSA. The transmitral flow velocity was obtained from apical four-chamber view with the pulsed Doppler method. The following parameters were measured: the peak early (E) and late (A) diastolic velocities, deceleration time (DecT) from the peak to baseline of the early diastolic transmitral flow velocity. The ratio of early diastolic to late diastolic mitral inflow velocities (E/A) was calculated. Flow propagation velocity (Vp), the rate of propagation of blood flowing from the mitral valve tips to the LV apex from apical four chamber, was also measured. All Doppler measurements were given as the average values of three consecutive cardiac cycles. The mitral annular motion velocity was recorded at the LV lateral and septal wall in the apical four-chamber view by pulsed tissue Doppler echocardiography. The means of peak early (Em) diastolic motion velocities were determined. E/Em was used as a surrogate for LV filling pressures. Left Atrial Strain Two-dimensional grayscale images of three cardiac cycles from apical four-chamber views were acquired using conventional ultrasound, with a frame rate of 60–90 frames/s (Fig. 1). The septal and lateral walls of the LA were consistently imaged without significant dropout. Examinations were performed by two experienced cardiologists who were blinded to the patient groups. We used off-line EchoPAc workstation to calculate LA strain and strain rate. The LA 2D-STE curves were obtained using R-wave onset of the electrocardiogram as a reference point. After defining the endocardial border manually, tracing was automatically developed by the software for each view. If the automatically obtained tracking segments were adequate for analysis, the software was allowed to read the data. For inadequate tracking segments, manual adjustments or changing software parameters were performed. Overall,
630 segments were analyzed (six segments for each subject) and a total of 3 % segments were excluded. Global LA strain and strain rate parameters were assessed as the average of six segmental values. QRS onset speckle-tracking echocardiography analysis for LA; LA peak strain just before mitral valve opening was taken as LA reservoir (LA-Res), and LA strain just before atrial contraction (onset of the P-wave on electrocardiography) was taken as LA-Pump. LA strain rate during ventricular systole (LA-SRs), LA-SRe during ventricular passive filling and LA-SRa during active atrial contraction were measured as LA function parameters (Fig. 1). Reproducibility Intraobserver reproducibility and interobserver reproducibility for both LA-Res and LA-Pump were assessed. For intraobserver assessment, images were re-analyzed after 1 month. The Bland–Altman analysis for interobserver reproducibility [mean difference, 95 % confidence interval (CI)] and intraobserver reproducibility [intraclass correlation coefficient (ICC), 95 % CI] was calculated. The interobserver and intraobserver agreement was assessed for LA-Res, 2.2 (-3.3 to 7.2) and 0.88 (0.82–0.92), respectively and LA-Pump 1.6 (-1.8 to 4.8) and 0.86, (0.77–0.90), respectively. Statistical Analysis Continuous and categorical variables were expressed as mean ± standard deviation (SD) and percentages, respectively. Continuous variables were compared using one-way ANOVA test as seen in Table 1. Tukey’s test was used for post hoc analyses. Analysis of covariance (ANCOVA) models included systolic and diastolic hypertension and age as covariates to statistically control for baseline differences in these variables in Tables 2 and 3. Categorical variables were compared using chi-square test (v2) or Fisher’s exact test, as appropriate. Spearman’s test was used for correlation analysis. A p value of \0.05 was regarded significant for all analyses. All the statistical tests were done using SPSS 11.5 (SPSS Inc., Chicago, IL, USA).
Results The characteristics of the study participants are shown in Table 1. The participants who consumed alcohol were all men, with a mean age of 39.8 ± 6.5 years (range 31–55 years). Post hoc analyses for age were controls versus group I, p = NS; controls versus group II, p \ 0.001; and group I versus group II, p = 0.001. Alcoholic patients had consumed a mean daily dose of ethanol of 185 ± 44 g (range 95–320 g) over a period of
123
Cardiovasc Toxicol Fig. 1 Left atrial strain (a) and strain rate (b) curves obtained from the apical four-chamber view in a patient. LA-Res: peak left atrial strain during ventricular systole, LA-Pump: peak left atrial strain during atrial systole, LA-SRs: peak left atrial strain rate during ventricular systole, LA-SRe: peak left atrial strain rate during early diastole, LA-SRa: peak left atrial strain rate during atrial systole
Table 1 General characteristics of the study participants
Variables
Healthy controls n = 30
a
Means group I versus healthy controls
b
Means group II versus Healthy Controls
123
p value
Group I n = 43
Group II n = 32
Age (years)
34.8 ± 5.8
37.5 ± 5.7
42.7 ± 6.4b
\0.001
Gender male (n, %)
30 (100)
43 (100)
32 (100)
1
2
BMI body mass index, BP blood pressure, AST aspartic acid transaminase, ALT alanine transaminase, TLDE total lifetime dose of ethanol
Alcoholic patients n = 75
BMI (kg/m )
26.1 ± 3.2
28.3 ± 4.9
28.6 ± 5.0
0.07
Creatinine (mg/dl)
0.86 ± 0.10
0.94 ± 0.14
0.95 ± 0.11b
0.05
Smokers (n, %)
13 (43.3)
25 (58.1)
18 (56.2)
0.363
Systolic BP (mmHg)
119.0 ± 8.4
124.9 ± 10.6a
133.2 ± 16.5b
0.001
Diastolic BP (mmHg)
75.5 ± 5.4
81.5 ± 8.8a
85.0 ± 11.9b
0.004
Glucose (mg/dl)
92 ± 10.8
95 ± 14.7
94.8 ± 13
0.77
Total cholesterol (mmol/l)
171.6 ± 29.2
191.1 ± 36.3
199.4 ± 61.1
0.17
Triglycerides (mmol/l)
132.8 ± 33.1
168.8 ± 51.1a
196.9 ± 74.8b
0.001
a
39.1 ± 13.5b
0.001
AST (U/l)
25.4 ± 8.7
38.4 ± 15.7
ALT (U/l) Hemoglobin (g/dl)
27.0 ± 10.3 14.2 ± 1.4
40.4 ± 14.4a 14.6 ± 1.3
43.9 ± 22.1b 14.7 ± 2.2
0.002 0.79 \0.001
Drinking histories Duration of heavy drinking (years)
None
11.5 ± 2.8
17.1 ± 3.6
Daily ethanol consumption (g)
None
174.4 ± 42.4
198.1 ± 43.6
0.002
TLDE (kg ethanol/kg body weight)
None
10.3 ± 3.1
17.0 ± 1.5
\0.001
Cardiovasc Toxicol Table 2 Comparisons of echocardiographic parameters between healthy controls and alcoholic patients Variables
Healthy controls n = 30
Alcoholic patients n = 75 Group I n = 43
LV-EDD (cm) LV-ESD (cm) LV mass index (g/m2)
p Group II n = 32
4.7 ± 0.4
4.9 ± 0.3a
5.1 ± 0.3b
0.005
3.1 ± 0.3
3.3 ± 0.2
a
3.4 ± 0.2b
0.008
67.6 ± 12.2
76.7 ± 14.1a
81.2 ± 15.1b
0.005
LV-EF (%)
63.4 ± 4.7
60.7 ± 5.9
61.1 ± 4.9
0.22
Cardiac index (l/min/m2)
3.83 ± 0.69
3.66 ± 0.70
3.44 ± 0.91b
0.034
170.9 ± 11.1
190.7 ± 32.4a
201.8 ± 26.7b
0.002
Vp
51.9 ± 6.9
43.9 ± 6.6a
40.6 ± 7.0b
E/A ratio
1.34 ± 0.19
1.11 ± 0.25a
1.09 ± 0.21b
\0.001
6.1 ± 1.5
7.3 ± 1.3a
8.2 ± 1.5b
\0.001
19.6 ± 2.1
a
25.7 ± 3.4b
\0.001
DecT
E/Em ratio 2
LAVI (ml/m )
23.9 ± 3.2
0.001
LV left ventricular, EDD end-diastolic diameter, ESD end-systolic diameter, DecT deceleration time from the peak to baseline of the early diastolic transmitral flow velocity, E/A ratio of peak early and late diastolic velocities, E/Em ratio of peak early mitral inflow velocity and peak early diastolic mitral annular velocity, EF ejection fraction, LAVI left atrial volume index, Vp velocity of propagation a
Means group I versus healthy controls
b
Means group II versus healthy controls
13.9 ± 4.3 years (range 6–27 years), with a mean TLDE of 13.2 ± 4.2 kg ethanol/kg body weight (3.9–20.2 kg/kg). In alcoholic patients, group I had six (14 %) and group II had eight (25 %) hypertensive patients. There was a significant difference between groups by terms of having hypertension (p = 0.04). All groups were similar in total cholesterol level; however, triglyceride, AST and ALT levels in the group II patients were significantly higher than the control group. Conventional Echocardiographic Measurements The echocardiographic variables are listed in Table 2. For LV mass index, Post hoc analyses revealed that controls versus group I, p = 0.05; controls versus group II, p = 0.004. However, there was no significant difference in LV mass index among the alcoholic groups. Compared to controls, alcoholic groups had a significant difference in LAVI. Nevertheless, no difference was observed across the alcoholic groups (controls vs. group I, p = 0.001, controls vs. group II, p = 0.001, group I vs. group II, p = NS). Diastolic function parameters showed differences between controls and alcoholic groups (Table 2). We compared these data between controls and alcoholic groups; we found no differences among the alcoholic groups (for DecT, E/A, Vp and E/Em, group I vs. group II, p = NS). Post hoc analyses revealed that for DecT, controls versus group I, p = 0.02, controls versus group II, p = 0.002; for E/A ratio, controls versus group I,
p = 0.001, controls versus group II, p = 0.002; for Vp, controls versus group I, p = 0.001, controls versus group II, p = 0.001; for E/Em, controls versus group I, p = 0.007, controls versus group II, p = 0.001. LA Functions in Chronic Alcoholism The LA myocardial parameters, reservoir and pump function, by 2D-STE are presented in Table 3. The LA-Res and LA-Pump were more significantly impaired in alcoholics (p \ 0.001 and p = 0.001, respectively) (Table 3). Post hoc analysis showed that for LA-Res, controls versus group I, p = 0.006; controls versus group II, p \ 0.001; group I versus group II, p = 0.01 (Fig. 2); for LA-Pump, controls versus group I, p = 0.03, controls versus group II, p \ 0.001, group I versus group II, p = 0.04. However, there were no differences in LA-SRs and LASRe between the controls and alcoholic groups. We performed corrections for age, systolic and diastolic blood pressure, smoking and BMI, which were known to affect LV diastolic function, with analysis of covariance. It is important to emphasize that studies should be adjusted for other potential determinants of the LV measurements, such as age, obesity, blood pressure and smoking status.
Discussion In the present study, for the first time, we described the LA function in chronic asymptomatic alcoholics by using 2D-
123
Cardiovasc Toxicol Table 3 Left atrial deformation parameters in healthy controls and alcoholic patients Variables
LA-Res LA-Pump
Healthy controls n = 30
Alcoholic patients n = 75 Group I n = 43
p
Group II n = 32
44.2 ± 7.2
38.1 ± 7.5a
33.3 ± 6.4b \0.001
18.1 ± 3.0
a
13.4 ± 3.8b \0.001
15.6 ± 3.7
LA-SRs
1.72 ± 0.42
1.52 ± 0.34
1.46 ± 0.41
0.08
LA-SRe
-1.50 ± 0.27
-1.46 ± 0.32
-1.34 ± 0.31
0.32
LA-SRa
-1.54 ± 0.36
-1.40 ± 0.25
-1.32 ± 0.35
0.27
LA left atrium, LA-Res peak left atrial strain during ventricular systole, LA-Pump peak left atrial strain during atrial systole, LA-SRs peak left atrial strain rate during ventricular systole, LA-SRe peak left atrial strain rate during early diastole, LA-SRa peak left atrial strain rate during atrial systole a
Means group I versus healthy controls
b
Means group II versus healthy controls
Fig. 2 Difference for the peak left atrial strain during ventricular systole (LA-Res) was found between healthy controls and group I and group II alcoholic patients
STE and conventional echocardiography. We demonstrated that compared with controls, alcoholic groups had more significantly impaired diastolic function. Moreover, no significant differences of LAVI, Vp and Doppler LV diastolic parameters, such as deceleration time, E/A and E/Em ratio, were observed among the alcoholic groups, whereas LA myocardial strain parameters were found significantly different. Chronic and excessive alcohol consumption causes structural and functional changes in the myocardium. It has been shown to have a deleterious impact on cardiac myofibril shortening and the composition of myoproteins [20]. Moreover, diastolic dysfunction appears to be an early finding in asymptomatic alcoholic patients [9, 10].
123
Impaired diastolic function contributes to the clinical picture of congestive heart failure. Parameters of LV diastolic function are powerful and important predictors of major cardiac events. Noninvasive parameters of diastolic function may give comparable information for the estimation of prognosis of asymptomatic alcoholic patients in order to initiate early therapy. Two-dimensional speckle-tracking echocardiography (2D-STE) is a novel non-Doppler-based technique for the angle independent and accurate quantification of myocardial deformation [12]. LA functions are divided into three phases in a cardiac cycle, namely: (1) a reservoir phase, which receives blood from the pulmonary veins during ventricular systole, (2) a passive conduit component during early diastole and (3) a pumping phase, with active contraction during late diastole. LA-Res values serve as a measure of LA compliance during the reservoir phase and LA-Pump as a measure of active atrial contraction. Increased LV filling pressure occurring as a result of LV diastolic dysfunction increases LA pressure and causes chamber dilatation. As a result, atrial remodeling occurs and atrial compliance and contractile functions decrease [12–14, 21]. Two-dimensional speckle-tracking longitudinal deformation imaging has showed accurate characterization of all phases of LA function. LA abnormalities are associated with abnormal diastolic function of the LV [21–23]. Chronically elevated LV filling pressures would lead to impaired LA longitudinal systolic and diastolic function. An inverse relationship between both reservoir and conduit functions and Doppler parameters of LV diastolic dysfunction and LV end-diastolic pressure has been demonstrated in patients with HF [24]. Wakami et al. [14] showed that elevated LV end-diastolic pressure is associated with a decrease of peak LA-Res. Peak atrial longitudinal strain has been shown to be associated with LV filling pressure [12]. Additionally, the longitudinal strain, which is inversely related to LA wall fibrosis, has been reported to be a feasible and reproducible method to assess LA myocardial function [15]. Although the effect of chronic alcoholism on systolic function is well established, diastolic involvement has been evaluated partially [8, 11]. Additionally, studies investigating the effects of chronic alcohol consumption on diastolic function have yielded conflicting results. Kupari et al. [10] demonstrated that diastolic dysfunction appears to be an early finding in asymptomatic alcoholic patients with a median 11 years of duration of drinking. However, they did not find any relation between the Doppler indexes and either duration of alcoholism or the quantity of the alcohol. Likewise, in the study conducted by Silberbauer et al. [7], no association was found between LV diastolic function and the duration or amount of chronic alcoholism. Another study showed no differences in impaired LV
Cardiovasc Toxicol
diastolic filling in chronic alcoholics by using M-Mode [4]. Moreover, Cerqueira et al. [6] showed no differences in LV diastolic function in asymptomatic alcoholics, whereas Ferna´ndez-Sola` et al. [8] found that there was a strong relationship between ethanol consumption and LV diastolic dysfunction, with a significant correlation between the TLDE and the decrease of E/A index. They concluded that alcohol had a negative effect on diastolic LV function in a dose-dependent manner. Likewise, Lazarevic´ et al. [11], who compared three different groups of alcoholic patients based on the duration of drinking, reported impaired LV relaxation in asymptomatic alcoholics. They also found relatively weak correlation between duration of drinking and DecT and E/A ratio. These discrepancies may be explained either differences in the severity of alcoholism or the method used to assess diastolic function. Another reason could be due to the limitations of the Doppler method. Doppler-derived indexes are load dependent, whereas 2DSTE provides non-Doppler, angle independent and objective quantification of myocardial deformation [25]. In this current study, we observed that chronic alcoholics had more significantly impaired LV diastolic dysfunction compared with controls. This is the first study to describe LA function in chronic alcoholics with using 2DSTE. In this respect, in our study, while there were no differences in diastolic dysfunction determined by conventional echocardiography among alcoholic groups, we found significant differences between alcoholics by terms of LA-Res and LA-Pump. LA myocardial impairment resulting from structural and functional alterations due to alcohol per se may play a role in the reduction of LA function. This reduction of LA strain values in alcoholics may be the result of the direct alcohol toxicity, alongside the diastolic dysfunction. Pathological LA wall remodeling and fibrosis results in low atrial compliance and elastance significantly increase the risk of developing permanent atrial fibrillation [26]. Thus, we can explain the increased risk for atrial fibrillation in this population. Recently, it has been shown that modest levels of alcohol consumption were associated with significant LA enlargement [27]. In general, asymptomatic alcoholic patients with changes in cardiac structure and function had a history of consuming [90 g/day of alcohol for [5 years [28]. However, the duration of drinking seems more important than daily alcohol consumption. Mathews et al. [29] showed that alcoholics with heart failure had a longer duration of drinking compared to the asymptomatic alcoholics (duration 10 years vs. at least 6 years, respectively), while the daily amount of alcohol consumption was comparable between the groups. Likewise, another study found in alcoholics with heart failure that the average duration of drinking 24.8 years and daily alcohol consumption
286 g/day were longer and higher compared to patients in the asymptomatic group, 16.2 years and 243 g/day. Since TLDE involves both duration and daily alcohol intake, we used estimated cumulative ethanol consumption TLDE in this study. Previously, it has been shown that LV mass was unrelated to alcohol, indicating that the functional and structural responses of the LV to chronic drinking may differ in time [30]. Similarly, we found no differences between alcoholic groups by terms of LV mass index. Chronic alcohol consumption deteriorated LV diastolic function irrespective of LV mass. It is important to emphasize that studies should be adjusted for other potential determinants, such as age, obesity, blood pressure and smoking status which were known to affect LV diastolic function. In this study, some of the alcoholic patients had concomitant hypertension, which also affects longitudinal function. To adjust the analyses for other potential determinants of the LV measurements, ANOVA test was used. Alcohol use is well known to increase blood pressure itself. In a study conducted by Lazarevic´ et al. [11] who investigated preclinical cardiac abnormalities in chronic alcoholics, they excluded patients with history of hypertension at the beginning of the study. Despite this exclusion criteria, hypertension was observed in 16 (52 %) patients with drinking history 5–9 years, in 16 (52 %) patients with drinking history 10–15 years and in 16 (59 %) patients with drinking history more than 15 years during hospital stay. Thus, exclusion of hypertensive or smoker alcoholic patients would produce significant bias in our results. The findings of current study indicate that the reduction in LA function with alcohol cannot be explained by covariates such as blood pressure, smoking or BMI which can influence LV diastolic function. Limitations A limitation of the present study was the relatively small study population. As only male subjects were included in our study, the effects of alcoholism on LV diastolic function in women were not assessed. Secondly, since there are no data related to the classification, we grouped patients into two groups according to TLDE, which should be useful to assess effects of alcohol intake on LA function. Alcoholic patients were considered to have a low probability of CAD based on physical examination, normal treadmill exercise testing and normal resting echocardiography. Thirdly, the data related to pulmonic vein flow which may help in the evaluation of both atrial reservoir function and compliance were not given in this study. Another limitation, this is a cross-sectional study. Moreover, there is no follow-up of these patients.
123
Cardiovasc Toxicol
Conclusion LA dysfunction, measured as LA-Res and LA-Pump function, may be a valuable clinical marker for decision making in chronic alcoholic patients, and heavy alcohol consumption may play an important role in LA function impairment. Conflict of interest
15.
16.
No conflicts of interest to disclose. 17.
References 18. 1. George, A., & Figueredo, V. M. (2011). Alcoholic cardiomyopathy: A review. Journal of Cardiac Failure, 17, 844–849. 2. Piano, M. R., & Phillips, S. A. (2014). Alcoholic cardiomyopathy: Pathophysiologic insights. Cardiovascular Toxicology [Epub ahead of print]. 3. Onat, A., Hergenc¸, G., Ku¨c¸u¨kdurmaz, Z., Ug˘ur, M., Kaya, Z., Can, G., et al. (2009). Moderate and heavy alcohol consumption among Turks: Long-term impact on mortality and cardiometabolic risk. Tu¨rk Kardiyoloji Derneg˘i ars¸ ivi, 37, 83–90. 4. Fabrizio, L., & Regan, T. J. (1994). Alcoholic cardiomyopathy. Cardiovascular Drugs and Therapy, 8, 89–94. 5. Dancy, M., Bland, J. M., Leech, G., Gaitonde, M. K., & Maxwell, J. D. (1985). Preclinical left ventricular abnormalities in alcoholics are independent of nutritional status, cirrhosis, and cigarette smoking. The Lancet, 1, 1122–1125. 6. Cerqueira, M. D., Harp, G. D., Ritchie, J. L., Stratton, J. R., & Walker, R. D. (1991). Rarity of preclinical alcoholic cardiomyopathy in chronic alcoholics less than 40 years of age. American Journal of Cardiology, 67, 183–187. 7. Silberbauer, K., Juhasz, M., Ohrenberger, G., & Hess, C. (1988). Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in young alcoholics. Cardiology, 75, 431–439. 8. Ferna´ndez-Sola`, J., Nicola´s, J. M., Pare´, J. C., Sacanella, E., Fatjo´, F., Cofa´n, M., et al. (2000). Diastolic function impairment in alcoholics. Alcoholism, Clinical and Experimental Research, 24, 1830–1835. 9. Kupari, M., Koskinen, P., Suokas, A., & Ventila¨, M. (1990). Left ventricular filling impairment in asymptomatic chronic alcoholics. American Journal of Cardiology, 66, 1473–1477. 10. Patel, H. C., Hayward, C., di Mario, C., Cowie, M. R., Lyon, A. R., & Rosen, S. D. (2014). Heart failure with preserved ejection fraction: The impact of stricter definitions. European Journal of Heart Failure, 16(7), 767–771. doi:10.1002/ejhf.106. 11. Lazarevic´, A. M., Nakatani, S., Neskovic´, A. N., Marinkovic´, J., Yasumura, Y., Stojicic´, D., et al. (2000). Early changes in left ventricular function in chronic asymptomatic alcoholics: Relation to the duration of heavy drinking. Journal of the American College of Cardiology, 35, 1599–1606. 12. Cameli, M., Lisi, M., Mondillo, S., Padeletti, M., Ballo, P., Tsioulpas, C., et al. (2010). Left atrial longitudinal strain by speckle tracking echocardiography correlates well with left ventricular filling pressures in patients with heart failure. Cardiovascular Ultrasound, 21(8), 14. 13. Galderisi, M., Henein, M. Y., D’hooge, J., Sicari, R., Badano, L. P., Zamorano, J. L., et al. (2011). Recommendations of the European Association of Echocardiography: How to use echoDoppler in clinical trials: Different modalities for different purposes. European Journal of Echocardiography, 12, 339–353. 14. Wakami, K., Ohte, N., Asada, K., Fukuta, H., Goto, T., Mukai, S., et al. (2009). Correlation between left ventricular end-diastolic
123
19.
20.
21.
22.
23.
24.
25.
26.
27.
28. 29.
30.
pressure and peak left atrial wall strain during left ventricular systole. Journal of the American Society of Echocardiography, 22, 847–851. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders-DMS-V (5th ed.). Washington, DC: American Psychiatric Association. Urbano-Marquez, A., Estruch, R., Navarro-Lopez, F., Grau, J. M., Mont, L., & Rubin, E. (1989). The effects of alcoholism on skeletal and cardiac muscle. New England Journal of Medicine, 320, 409–415. Nagueh, S. F., Appleton, C. P., Gillebert, T. C., Marino, P. N., Oh, J. K., Smiseth, O. A., et al. (2009). Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Journal of the American Society of Echocardiography, 22, 107–133. Devereux, R. B., Alonso, D. R., Lutas, E. M., Gottlieb, G. J., Campo, E., Sachs, I., et al. (1986). Echocardiographic assessment of left ventricular hypertrophy: Comparison to necropsy findings. American Journal of Cardiology, 57, 450–458. Pritchett, A. M., Jacobsen, S. J., Mahoney, D. W., Rodeheffer, R. J., Bailey, K. R., & Redfield, M. M. (2003). Left atrial volume as an index of left atrial size: A population-based study. Journal of the American College of Cardiology, 41, 1036–1043. Iacovoni, A., De Maria, R., & Gavazzi, A. (2010). Alcoholic cardiomyopathy. Journal of Cardiovascular Medicine (Hagerstown, Maryland), 11, 884–892. Morris, D. A., Gailani, M., Vaz Pe´rez, A., Blaschke, F., Dietz, R., Haverkamp, W., et al. (2011). Left atrial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. Journal of the American Society of Echocardiography, 24, 651–662. Santos, A. B., Kraigher-Krainer, E., Gupta, D. K., Claggett, B., Zile, M. R., Pieske, B., et al. (2014). Impaired left atrial function in heart failure with preserved ejection fraction. European Journal of Heart Failure. doi:10.1002/ejhf.147. Kocabay, G., Karabay, C. Y., Colak, Y., Oduncu, V., Kalayci, A., Akgun, T., et al. (2014). Left atrial deformation parameters in patients with non-alcoholic fatty liver disease: A 2D speckle tracking imaging study. Clinical science (London), 126(4), 297–304. Todaro, M. C., Choudhuri, I., Belohlavek, M., Jahangir, A., Carerj, S., Oreto, L., et al. (2012). New echocardiographic techniques for evaluation of left atrial mechanics. European Heart Journal Cardiovascular Imaging, 13, 973–984. Mondillo, S., Galderisi, M., Mele, D., Cameli, M., Lomoriello, V. S., Zaca`, V., et al. (2011). Speckle-tracking echocardiography: A new technique for assessing myocardial function. Journal of Ultrasound in Medicine, 30, 71–83. Tan, T. C., Koutsogeorgis, I. D., Grapsa, J., Papadopoulos, C., Katsivas, A., Nihoyannopoulos, P., et al. (2014). Left atrium and the imaging of atrial fibrosis: Catch it if you can! European Journal of Clinical Investigation. doi:10.1111/eci.12305. Singh, K. J., Cohen, B. E., Na, B., Regan, M., Schiller, N. B., & Whooley, M. A. (2013). Alcohol consumption and 5-year change in left atrial volume among patients with coronary heart disease: Results from the Heart and Soul study. Journal of Cardiac Failure, 19, 183–189. Piano, M. R. (2002). Alcoholic cardiomyopathy: Incidence, clinical characteristics, and pathophysiology. Chest, 121, 1638–1650. Mathews, E. C, Jr., Gardin, J. M., Henry, W. L., Del Negro, A. A., Fletcher, R. D., Snow, J. A., et al. (1981). Echocardiographic abnormalities in chronic alcoholics with and without overt congestive heart failure. American Journal of Cardiology, 47, 570–578. Kupari, M., & Koskinen, P. (1993). Relation of left ventricular function to habitual alcohol consumption. American Journal of Cardiology, 72, 1418–1424.
ORIGINAL RESEARCH
Left Atrial Function by Speckle-Tracking Echocardiography in Chronic Asymptomatic Alcoholic Patients Gonenc Kocabay • Can Yucel Karabay • Arzu Kalaycı • Vecih Oduncu • Taylan Akgun • Ahmet Guler • Alev Kılıcgedik • Sedat Kalkan • Akin I˙zgi • Cevat Kırma
Ó Springer Science+Business Media New York 2014
Abstract Although the effects of chronic alcoholism on left ventricular (LV) systolic function are well established, diastolic impairment has been evaluated partially. In addition, there are scarce data available about the relation of LV diastolic function to either or both duration and quantity of drinking among alcoholics. The aim of the study was to evaluate the left atrial (LA) function in chronic asymptomatic alcoholic patients by using two-dimensional speckle-tracking echocardiography (2D-STE). We enrolled 30 healthy subjects (age 34.8 ± 5.8 years) and 75 asymptomatic male alcoholics (age 39.8 ± 6.5 years) divided into two groups, according to total lifetime dose of ethanol: group I,\15 kg/kg and group II, C15 kg/kg. In the 2D-STE analysis of the LA, strain during ventricular systole (LARes), during late diastole (LA-Pump) and strain rate during ventricular contraction (LA-SRs), during passive ventricular filling (LA-SRe), during active atrial contraction (LASRa) were obtained. Deceleration time was longer, E/A and Vp were smaller, and E/Em was higher in alcoholics. Although parameters of diastolic dysfunction were comparable in alcoholic groups, LA-Res and LA-Pump were found significantly different among the alcoholics. However, there were no differences in LA-SRs and LA-SRe between the controls and alcoholic groups. LA function is reduced in chronic alcohol abuse, and heavy alcohol consumption may play an important role in LA function impairment.
G. Kocabay (&) C. Y. Karabay A. Kalaycı V. Oduncu T. Akgun A. Guler A. Kılıcgedik S. Kalkan A. ˙Izgi C. Kırma Cardiology Department, Kartal Kosuyolu Heart and Research Hospital, Istanbul, Turkey e-mail: [email protected]
Keywords Left atrial function LV diastolic dysfunction Speckle-tracking echocardiography Chronic asymptomatic alcoholic patients
Introduction Chronic excessive alcohol consumption is a risk factor for developing dilated cardiomyopathy, independently of coronary atherosclerosis and hypertension [1–3]. The subclinical changes of left ventricular (LV) function in noncardiac alcoholics are frequently diastolic rather than systolic abnormality [4]. However, there are scarce data available about the relation of LV diastolic function to either or both duration and quantity of drinking among alcoholics. Studies investigating LV diastolic dysfunction have yielded conflicting results. While some studies found the normal LV filling [3–6], some of them reported impaired LV filling [7–11]. Possible reasons for these discrepancies may be due to the different methods used to assess diastolic function. Studies investigating diastolic function in alcoholics used only transmitral velocity (E/A ratio and deceleration time). Since these parameters are dependent on rate, blood pressure and load (volume), the results may be not diagnostic of diastolic dysfunction. Two-dimensional speckle-tracking echocardiography (2D-STE) is a novel non-Doppler-based method for the angle independent and accurate quantification of myocardial deformation. It has the advantage of being angle independent and to be relatively load-independent indices [12, 13]. With the advent of 2D-STE, we are able to detect early left atrial (LA) dysfunction even before structural changes occur. LA abnormalities are associated with abnormal diastolic dysfunction of the LV. 2D-STE provides the quantification of longitudinal myocardial LA
123
Cardiovasc Toxicol
deformation dynamics, which was recently proposed as an alternative approach for the LV filling pressure estimation [13]. Hence, the aim of the present study was to investigate LA function in chronic alcoholic patients using a combination of 2D-STE and conventional echocardiography, i.e., Doppler-derived indexes and LA volume.
Methods Study Population Between 2010 and 2011, we selected 90 alcoholic male patients who were admitted to the outpatient alcoholism unit for assistance in terminating their dependence on alcohol. The study protocol was approved by the Institutional Review Board of the Hospital, and each subject gave informed written consent to participate. Inclusion criteria were as follows: (1) positive diagnostic criteria for alcohol abuse established by the American Psychiatric Association [14], (2) daily ethanol consumption C90 g and C4 days/week, (3) drinking history C5 years, (4) normal sinus rhythm. Exclusion criteria were as follows: (1) impairment of LV systolic function (ejection fraction, EF \50 %) by using echocardiographic evaluation, (2) patients with previous history of coronary artery disease (CAD, defined as any degree of CAD on previous angiogram or history of myocardial infarction or angina), (3) patients with chronic liver disease or renal dysfunction, (4) history of palpitation or any documented rhythm abnormalities, i.e., supraventricular arrhythmia, on 24-h Holter examination. Of these, five patients with inadequate echocardiographic images, four patients with paroxysmal atrial tachycardia on 24-h Holter examination and three patients with conflicting amount of ethanol intake were excluded from the study. In addition, three patients with positive clinical diagnosis of the liver damage were excluded. For this diagnosis, besides laboratory measurements, the presence of three or more of the following physical findings was used: tender hepatomegaly, palmar erythema, spider angiomata, gynecomastia, and cases having cirrhosis, splenomegaly, ascites and evidence of collaterals on the abdomen were examined. A total of 75 consecutive asymptomatic male alcoholics (age 39.8 ± 6.5 years, age ranged 31–55 years) were enrolled in this study. All patients with their families and friends were questioned by experienced psychiatrists about the total duration of heavy alcohol drinking, and the type and amount of drinks consumed per day. Daily ethanol consumption was obtained by converting the type and amount of alcoholic beverages to grams of absolute ethanol. Alcohol consumption was expressed in grams per day. In order to
123
calculate the total dose of ethanol consumed in their lifetime (total lifetime dose of ethanol, TLDE), this was expressed in kg of ethanol/kg of body weight and was estimated by first multiplying the daily consumption of ethanol by the number of days of the periods of exposure to alcohol and then dividing the product by the body weight of the patient when first admitted. Since TLDE was reported to be a good predictor of LV function in alcoholic patients [8, 16], in advance of data collection, we decided to classify alcoholic patients into two groups according to the TLDE values: group I (TLDE \15 kg ethanol/kg body weight) and group II (TLDE C15 kg ethanol/kg body weight). Because there is no cutoff value for TLDE or other markers such as, duration of drinking and daily alcohol consumption, in this article, we calculated the cutoff level for TLDE as presuming that someone (male gender) is 80–85 kg and drinking more than 17 years (average of 15 and 20 years, coming from previous studies). After the mathematical calculation described above, we found ‘‘15’’ as a cutoff level. Current smokers (more than ten number of cigarettes consumed daily) were recorded. Thirty healthy male controls (age 34.8 ± 5.8 years; controls vs. group I, p = NS; controls vs. group II, p \ 0.001) without drinking histories were evaluated as the control group. None of them had a history of hypertension, diabetes mellitus, dyslipidemia nor any history, signs or symptoms of cardiovascular diseases. Clinical and Laboratory Evaluations A complete physical examination was performed to all subjects. Anthropometric assessments of height and weight were measured, and body mass index (BMI, kg/m2) and body surface area (BSA, m2) were calculated. Blood pressures were measured after 10 min of rest in a quite room. Venous blood samples were taken in the morning after a 12-h fasting. Complete blood counts and biochemical parameters, such as serum glucose, creatinine, total cholesterol and triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were assessed. A 12-lead standard resting electrocardiogram and exercise treadmill stress testing were performed in all patients according to the modified Bruce protocol to exclude the presence of silent myocardial ischemia or significant disturbances of sinus rhythm. None of them had any abnormal test results. Conventional, Pulsed Doppler and Tissue Doppler Echocardiography All echocardiographic measurements were taken by using a commercially available ultrasound system (GE-Vivid 7
Cardiovasc Toxicol
system, Horten, Norway) with a 3.5-MHz transducer. All data were transferred to a workstation for further offline analysis (EchoPAc, GE, Horten, Norway). All measurements and evaluation were taken according to the guidelines of American Society of Echocardiography [17]. The LV end-diastolic diameter (EDD), end-systolic diameter (ESD), end-diastolic thickness of ventricular septum (IVS) and end-diastolic thickness of LV posterior wall (PWT) were measured by M-Mode echocardiography. Using these parameters, we calculated LV mass (g) by the Devereux formula [18]. LV mass index was then determined by dividing the LV mass measurement by the BSA (g/m2). LV-EF was calculated by using Simpson’s method. The LA volume was measured by using the biplane arealength method [19]. The indexed volume of LA (LAVI) was calculated as LA volume/BSA. The transmitral flow velocity was obtained from apical four-chamber view with the pulsed Doppler method. The following parameters were measured: the peak early (E) and late (A) diastolic velocities, deceleration time (DecT) from the peak to baseline of the early diastolic transmitral flow velocity. The ratio of early diastolic to late diastolic mitral inflow velocities (E/A) was calculated. Flow propagation velocity (Vp), the rate of propagation of blood flowing from the mitral valve tips to the LV apex from apical four chamber, was also measured. All Doppler measurements were given as the average values of three consecutive cardiac cycles. The mitral annular motion velocity was recorded at the LV lateral and septal wall in the apical four-chamber view by pulsed tissue Doppler echocardiography. The means of peak early (Em) diastolic motion velocities were determined. E/Em was used as a surrogate for LV filling pressures. Left Atrial Strain Two-dimensional grayscale images of three cardiac cycles from apical four-chamber views were acquired using conventional ultrasound, with a frame rate of 60–90 frames/s (Fig. 1). The septal and lateral walls of the LA were consistently imaged without significant dropout. Examinations were performed by two experienced cardiologists who were blinded to the patient groups. We used off-line EchoPAc workstation to calculate LA strain and strain rate. The LA 2D-STE curves were obtained using R-wave onset of the electrocardiogram as a reference point. After defining the endocardial border manually, tracing was automatically developed by the software for each view. If the automatically obtained tracking segments were adequate for analysis, the software was allowed to read the data. For inadequate tracking segments, manual adjustments or changing software parameters were performed. Overall,
630 segments were analyzed (six segments for each subject) and a total of 3 % segments were excluded. Global LA strain and strain rate parameters were assessed as the average of six segmental values. QRS onset speckle-tracking echocardiography analysis for LA; LA peak strain just before mitral valve opening was taken as LA reservoir (LA-Res), and LA strain just before atrial contraction (onset of the P-wave on electrocardiography) was taken as LA-Pump. LA strain rate during ventricular systole (LA-SRs), LA-SRe during ventricular passive filling and LA-SRa during active atrial contraction were measured as LA function parameters (Fig. 1). Reproducibility Intraobserver reproducibility and interobserver reproducibility for both LA-Res and LA-Pump were assessed. For intraobserver assessment, images were re-analyzed after 1 month. The Bland–Altman analysis for interobserver reproducibility [mean difference, 95 % confidence interval (CI)] and intraobserver reproducibility [intraclass correlation coefficient (ICC), 95 % CI] was calculated. The interobserver and intraobserver agreement was assessed for LA-Res, 2.2 (-3.3 to 7.2) and 0.88 (0.82–0.92), respectively and LA-Pump 1.6 (-1.8 to 4.8) and 0.86, (0.77–0.90), respectively. Statistical Analysis Continuous and categorical variables were expressed as mean ± standard deviation (SD) and percentages, respectively. Continuous variables were compared using one-way ANOVA test as seen in Table 1. Tukey’s test was used for post hoc analyses. Analysis of covariance (ANCOVA) models included systolic and diastolic hypertension and age as covariates to statistically control for baseline differences in these variables in Tables 2 and 3. Categorical variables were compared using chi-square test (v2) or Fisher’s exact test, as appropriate. Spearman’s test was used for correlation analysis. A p value of \0.05 was regarded significant for all analyses. All the statistical tests were done using SPSS 11.5 (SPSS Inc., Chicago, IL, USA).
Results The characteristics of the study participants are shown in Table 1. The participants who consumed alcohol were all men, with a mean age of 39.8 ± 6.5 years (range 31–55 years). Post hoc analyses for age were controls versus group I, p = NS; controls versus group II, p \ 0.001; and group I versus group II, p = 0.001. Alcoholic patients had consumed a mean daily dose of ethanol of 185 ± 44 g (range 95–320 g) over a period of
123
Cardiovasc Toxicol Fig. 1 Left atrial strain (a) and strain rate (b) curves obtained from the apical four-chamber view in a patient. LA-Res: peak left atrial strain during ventricular systole, LA-Pump: peak left atrial strain during atrial systole, LA-SRs: peak left atrial strain rate during ventricular systole, LA-SRe: peak left atrial strain rate during early diastole, LA-SRa: peak left atrial strain rate during atrial systole
Table 1 General characteristics of the study participants
Variables
Healthy controls n = 30
a
Means group I versus healthy controls
b
Means group II versus Healthy Controls
123
p value
Group I n = 43
Group II n = 32
Age (years)
34.8 ± 5.8
37.5 ± 5.7
42.7 ± 6.4b
\0.001
Gender male (n, %)
30 (100)
43 (100)
32 (100)
1
2
BMI body mass index, BP blood pressure, AST aspartic acid transaminase, ALT alanine transaminase, TLDE total lifetime dose of ethanol
Alcoholic patients n = 75
BMI (kg/m )
26.1 ± 3.2
28.3 ± 4.9
28.6 ± 5.0
0.07
Creatinine (mg/dl)
0.86 ± 0.10
0.94 ± 0.14
0.95 ± 0.11b
0.05
Smokers (n, %)
13 (43.3)
25 (58.1)
18 (56.2)
0.363
Systolic BP (mmHg)
119.0 ± 8.4
124.9 ± 10.6a
133.2 ± 16.5b
0.001
Diastolic BP (mmHg)
75.5 ± 5.4
81.5 ± 8.8a
85.0 ± 11.9b
0.004
Glucose (mg/dl)
92 ± 10.8
95 ± 14.7
94.8 ± 13
0.77
Total cholesterol (mmol/l)
171.6 ± 29.2
191.1 ± 36.3
199.4 ± 61.1
0.17
Triglycerides (mmol/l)
132.8 ± 33.1
168.8 ± 51.1a
196.9 ± 74.8b
0.001
a
39.1 ± 13.5b
0.001
AST (U/l)
25.4 ± 8.7
38.4 ± 15.7
ALT (U/l) Hemoglobin (g/dl)
27.0 ± 10.3 14.2 ± 1.4
40.4 ± 14.4a 14.6 ± 1.3
43.9 ± 22.1b 14.7 ± 2.2
0.002 0.79 \0.001
Drinking histories Duration of heavy drinking (years)
None
11.5 ± 2.8
17.1 ± 3.6
Daily ethanol consumption (g)
None
174.4 ± 42.4
198.1 ± 43.6
0.002
TLDE (kg ethanol/kg body weight)
None
10.3 ± 3.1
17.0 ± 1.5
\0.001
Cardiovasc Toxicol Table 2 Comparisons of echocardiographic parameters between healthy controls and alcoholic patients Variables
Healthy controls n = 30
Alcoholic patients n = 75 Group I n = 43
LV-EDD (cm) LV-ESD (cm) LV mass index (g/m2)
p Group II n = 32
4.7 ± 0.4
4.9 ± 0.3a
5.1 ± 0.3b
0.005
3.1 ± 0.3
3.3 ± 0.2
a
3.4 ± 0.2b
0.008
67.6 ± 12.2
76.7 ± 14.1a
81.2 ± 15.1b
0.005
LV-EF (%)
63.4 ± 4.7
60.7 ± 5.9
61.1 ± 4.9
0.22
Cardiac index (l/min/m2)
3.83 ± 0.69
3.66 ± 0.70
3.44 ± 0.91b
0.034
170.9 ± 11.1
190.7 ± 32.4a
201.8 ± 26.7b
0.002
Vp
51.9 ± 6.9
43.9 ± 6.6a
40.6 ± 7.0b
E/A ratio
1.34 ± 0.19
1.11 ± 0.25a
1.09 ± 0.21b
\0.001
6.1 ± 1.5
7.3 ± 1.3a
8.2 ± 1.5b
\0.001
19.6 ± 2.1
a
25.7 ± 3.4b
\0.001
DecT
E/Em ratio 2
LAVI (ml/m )
23.9 ± 3.2
0.001
LV left ventricular, EDD end-diastolic diameter, ESD end-systolic diameter, DecT deceleration time from the peak to baseline of the early diastolic transmitral flow velocity, E/A ratio of peak early and late diastolic velocities, E/Em ratio of peak early mitral inflow velocity and peak early diastolic mitral annular velocity, EF ejection fraction, LAVI left atrial volume index, Vp velocity of propagation a
Means group I versus healthy controls
b
Means group II versus healthy controls
13.9 ± 4.3 years (range 6–27 years), with a mean TLDE of 13.2 ± 4.2 kg ethanol/kg body weight (3.9–20.2 kg/kg). In alcoholic patients, group I had six (14 %) and group II had eight (25 %) hypertensive patients. There was a significant difference between groups by terms of having hypertension (p = 0.04). All groups were similar in total cholesterol level; however, triglyceride, AST and ALT levels in the group II patients were significantly higher than the control group. Conventional Echocardiographic Measurements The echocardiographic variables are listed in Table 2. For LV mass index, Post hoc analyses revealed that controls versus group I, p = 0.05; controls versus group II, p = 0.004. However, there was no significant difference in LV mass index among the alcoholic groups. Compared to controls, alcoholic groups had a significant difference in LAVI. Nevertheless, no difference was observed across the alcoholic groups (controls vs. group I, p = 0.001, controls vs. group II, p = 0.001, group I vs. group II, p = NS). Diastolic function parameters showed differences between controls and alcoholic groups (Table 2). We compared these data between controls and alcoholic groups; we found no differences among the alcoholic groups (for DecT, E/A, Vp and E/Em, group I vs. group II, p = NS). Post hoc analyses revealed that for DecT, controls versus group I, p = 0.02, controls versus group II, p = 0.002; for E/A ratio, controls versus group I,
p = 0.001, controls versus group II, p = 0.002; for Vp, controls versus group I, p = 0.001, controls versus group II, p = 0.001; for E/Em, controls versus group I, p = 0.007, controls versus group II, p = 0.001. LA Functions in Chronic Alcoholism The LA myocardial parameters, reservoir and pump function, by 2D-STE are presented in Table 3. The LA-Res and LA-Pump were more significantly impaired in alcoholics (p \ 0.001 and p = 0.001, respectively) (Table 3). Post hoc analysis showed that for LA-Res, controls versus group I, p = 0.006; controls versus group II, p \ 0.001; group I versus group II, p = 0.01 (Fig. 2); for LA-Pump, controls versus group I, p = 0.03, controls versus group II, p \ 0.001, group I versus group II, p = 0.04. However, there were no differences in LA-SRs and LASRe between the controls and alcoholic groups. We performed corrections for age, systolic and diastolic blood pressure, smoking and BMI, which were known to affect LV diastolic function, with analysis of covariance. It is important to emphasize that studies should be adjusted for other potential determinants of the LV measurements, such as age, obesity, blood pressure and smoking status.
Discussion In the present study, for the first time, we described the LA function in chronic asymptomatic alcoholics by using 2D-
123
Cardiovasc Toxicol Table 3 Left atrial deformation parameters in healthy controls and alcoholic patients Variables
LA-Res LA-Pump
Healthy controls n = 30
Alcoholic patients n = 75 Group I n = 43
p
Group II n = 32
44.2 ± 7.2
38.1 ± 7.5a
33.3 ± 6.4b \0.001
18.1 ± 3.0
a
13.4 ± 3.8b \0.001
15.6 ± 3.7
LA-SRs
1.72 ± 0.42
1.52 ± 0.34
1.46 ± 0.41
0.08
LA-SRe
-1.50 ± 0.27
-1.46 ± 0.32
-1.34 ± 0.31
0.32
LA-SRa
-1.54 ± 0.36
-1.40 ± 0.25
-1.32 ± 0.35
0.27
LA left atrium, LA-Res peak left atrial strain during ventricular systole, LA-Pump peak left atrial strain during atrial systole, LA-SRs peak left atrial strain rate during ventricular systole, LA-SRe peak left atrial strain rate during early diastole, LA-SRa peak left atrial strain rate during atrial systole a
Means group I versus healthy controls
b
Means group II versus healthy controls
Fig. 2 Difference for the peak left atrial strain during ventricular systole (LA-Res) was found between healthy controls and group I and group II alcoholic patients
STE and conventional echocardiography. We demonstrated that compared with controls, alcoholic groups had more significantly impaired diastolic function. Moreover, no significant differences of LAVI, Vp and Doppler LV diastolic parameters, such as deceleration time, E/A and E/Em ratio, were observed among the alcoholic groups, whereas LA myocardial strain parameters were found significantly different. Chronic and excessive alcohol consumption causes structural and functional changes in the myocardium. It has been shown to have a deleterious impact on cardiac myofibril shortening and the composition of myoproteins [20]. Moreover, diastolic dysfunction appears to be an early finding in asymptomatic alcoholic patients [9, 10].
123
Impaired diastolic function contributes to the clinical picture of congestive heart failure. Parameters of LV diastolic function are powerful and important predictors of major cardiac events. Noninvasive parameters of diastolic function may give comparable information for the estimation of prognosis of asymptomatic alcoholic patients in order to initiate early therapy. Two-dimensional speckle-tracking echocardiography (2D-STE) is a novel non-Doppler-based technique for the angle independent and accurate quantification of myocardial deformation [12]. LA functions are divided into three phases in a cardiac cycle, namely: (1) a reservoir phase, which receives blood from the pulmonary veins during ventricular systole, (2) a passive conduit component during early diastole and (3) a pumping phase, with active contraction during late diastole. LA-Res values serve as a measure of LA compliance during the reservoir phase and LA-Pump as a measure of active atrial contraction. Increased LV filling pressure occurring as a result of LV diastolic dysfunction increases LA pressure and causes chamber dilatation. As a result, atrial remodeling occurs and atrial compliance and contractile functions decrease [12–14, 21]. Two-dimensional speckle-tracking longitudinal deformation imaging has showed accurate characterization of all phases of LA function. LA abnormalities are associated with abnormal diastolic function of the LV [21–23]. Chronically elevated LV filling pressures would lead to impaired LA longitudinal systolic and diastolic function. An inverse relationship between both reservoir and conduit functions and Doppler parameters of LV diastolic dysfunction and LV end-diastolic pressure has been demonstrated in patients with HF [24]. Wakami et al. [14] showed that elevated LV end-diastolic pressure is associated with a decrease of peak LA-Res. Peak atrial longitudinal strain has been shown to be associated with LV filling pressure [12]. Additionally, the longitudinal strain, which is inversely related to LA wall fibrosis, has been reported to be a feasible and reproducible method to assess LA myocardial function [15]. Although the effect of chronic alcoholism on systolic function is well established, diastolic involvement has been evaluated partially [8, 11]. Additionally, studies investigating the effects of chronic alcohol consumption on diastolic function have yielded conflicting results. Kupari et al. [10] demonstrated that diastolic dysfunction appears to be an early finding in asymptomatic alcoholic patients with a median 11 years of duration of drinking. However, they did not find any relation between the Doppler indexes and either duration of alcoholism or the quantity of the alcohol. Likewise, in the study conducted by Silberbauer et al. [7], no association was found between LV diastolic function and the duration or amount of chronic alcoholism. Another study showed no differences in impaired LV
Cardiovasc Toxicol
diastolic filling in chronic alcoholics by using M-Mode [4]. Moreover, Cerqueira et al. [6] showed no differences in LV diastolic function in asymptomatic alcoholics, whereas Ferna´ndez-Sola` et al. [8] found that there was a strong relationship between ethanol consumption and LV diastolic dysfunction, with a significant correlation between the TLDE and the decrease of E/A index. They concluded that alcohol had a negative effect on diastolic LV function in a dose-dependent manner. Likewise, Lazarevic´ et al. [11], who compared three different groups of alcoholic patients based on the duration of drinking, reported impaired LV relaxation in asymptomatic alcoholics. They also found relatively weak correlation between duration of drinking and DecT and E/A ratio. These discrepancies may be explained either differences in the severity of alcoholism or the method used to assess diastolic function. Another reason could be due to the limitations of the Doppler method. Doppler-derived indexes are load dependent, whereas 2DSTE provides non-Doppler, angle independent and objective quantification of myocardial deformation [25]. In this current study, we observed that chronic alcoholics had more significantly impaired LV diastolic dysfunction compared with controls. This is the first study to describe LA function in chronic alcoholics with using 2DSTE. In this respect, in our study, while there were no differences in diastolic dysfunction determined by conventional echocardiography among alcoholic groups, we found significant differences between alcoholics by terms of LA-Res and LA-Pump. LA myocardial impairment resulting from structural and functional alterations due to alcohol per se may play a role in the reduction of LA function. This reduction of LA strain values in alcoholics may be the result of the direct alcohol toxicity, alongside the diastolic dysfunction. Pathological LA wall remodeling and fibrosis results in low atrial compliance and elastance significantly increase the risk of developing permanent atrial fibrillation [26]. Thus, we can explain the increased risk for atrial fibrillation in this population. Recently, it has been shown that modest levels of alcohol consumption were associated with significant LA enlargement [27]. In general, asymptomatic alcoholic patients with changes in cardiac structure and function had a history of consuming [90 g/day of alcohol for [5 years [28]. However, the duration of drinking seems more important than daily alcohol consumption. Mathews et al. [29] showed that alcoholics with heart failure had a longer duration of drinking compared to the asymptomatic alcoholics (duration 10 years vs. at least 6 years, respectively), while the daily amount of alcohol consumption was comparable between the groups. Likewise, another study found in alcoholics with heart failure that the average duration of drinking 24.8 years and daily alcohol consumption
286 g/day were longer and higher compared to patients in the asymptomatic group, 16.2 years and 243 g/day. Since TLDE involves both duration and daily alcohol intake, we used estimated cumulative ethanol consumption TLDE in this study. Previously, it has been shown that LV mass was unrelated to alcohol, indicating that the functional and structural responses of the LV to chronic drinking may differ in time [30]. Similarly, we found no differences between alcoholic groups by terms of LV mass index. Chronic alcohol consumption deteriorated LV diastolic function irrespective of LV mass. It is important to emphasize that studies should be adjusted for other potential determinants, such as age, obesity, blood pressure and smoking status which were known to affect LV diastolic function. In this study, some of the alcoholic patients had concomitant hypertension, which also affects longitudinal function. To adjust the analyses for other potential determinants of the LV measurements, ANOVA test was used. Alcohol use is well known to increase blood pressure itself. In a study conducted by Lazarevic´ et al. [11] who investigated preclinical cardiac abnormalities in chronic alcoholics, they excluded patients with history of hypertension at the beginning of the study. Despite this exclusion criteria, hypertension was observed in 16 (52 %) patients with drinking history 5–9 years, in 16 (52 %) patients with drinking history 10–15 years and in 16 (59 %) patients with drinking history more than 15 years during hospital stay. Thus, exclusion of hypertensive or smoker alcoholic patients would produce significant bias in our results. The findings of current study indicate that the reduction in LA function with alcohol cannot be explained by covariates such as blood pressure, smoking or BMI which can influence LV diastolic function. Limitations A limitation of the present study was the relatively small study population. As only male subjects were included in our study, the effects of alcoholism on LV diastolic function in women were not assessed. Secondly, since there are no data related to the classification, we grouped patients into two groups according to TLDE, which should be useful to assess effects of alcohol intake on LA function. Alcoholic patients were considered to have a low probability of CAD based on physical examination, normal treadmill exercise testing and normal resting echocardiography. Thirdly, the data related to pulmonic vein flow which may help in the evaluation of both atrial reservoir function and compliance were not given in this study. Another limitation, this is a cross-sectional study. Moreover, there is no follow-up of these patients.
123
Cardiovasc Toxicol
Conclusion LA dysfunction, measured as LA-Res and LA-Pump function, may be a valuable clinical marker for decision making in chronic alcoholic patients, and heavy alcohol consumption may play an important role in LA function impairment. Conflict of interest
15.
16.
No conflicts of interest to disclose. 17.
References 18. 1. George, A., & Figueredo, V. M. (2011). Alcoholic cardiomyopathy: A review. Journal of Cardiac Failure, 17, 844–849. 2. Piano, M. R., & Phillips, S. A. (2014). Alcoholic cardiomyopathy: Pathophysiologic insights. Cardiovascular Toxicology [Epub ahead of print]. 3. Onat, A., Hergenc¸, G., Ku¨c¸u¨kdurmaz, Z., Ug˘ur, M., Kaya, Z., Can, G., et al. (2009). Moderate and heavy alcohol consumption among Turks: Long-term impact on mortality and cardiometabolic risk. Tu¨rk Kardiyoloji Derneg˘i ars¸ ivi, 37, 83–90. 4. Fabrizio, L., & Regan, T. J. (1994). Alcoholic cardiomyopathy. Cardiovascular Drugs and Therapy, 8, 89–94. 5. Dancy, M., Bland, J. M., Leech, G., Gaitonde, M. K., & Maxwell, J. D. (1985). Preclinical left ventricular abnormalities in alcoholics are independent of nutritional status, cirrhosis, and cigarette smoking. The Lancet, 1, 1122–1125. 6. Cerqueira, M. D., Harp, G. D., Ritchie, J. L., Stratton, J. R., & Walker, R. D. (1991). Rarity of preclinical alcoholic cardiomyopathy in chronic alcoholics less than 40 years of age. American Journal of Cardiology, 67, 183–187. 7. Silberbauer, K., Juhasz, M., Ohrenberger, G., & Hess, C. (1988). Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in young alcoholics. Cardiology, 75, 431–439. 8. Ferna´ndez-Sola`, J., Nicola´s, J. M., Pare´, J. C., Sacanella, E., Fatjo´, F., Cofa´n, M., et al. (2000). Diastolic function impairment in alcoholics. Alcoholism, Clinical and Experimental Research, 24, 1830–1835. 9. Kupari, M., Koskinen, P., Suokas, A., & Ventila¨, M. (1990). Left ventricular filling impairment in asymptomatic chronic alcoholics. American Journal of Cardiology, 66, 1473–1477. 10. Patel, H. C., Hayward, C., di Mario, C., Cowie, M. R., Lyon, A. R., & Rosen, S. D. (2014). Heart failure with preserved ejection fraction: The impact of stricter definitions. European Journal of Heart Failure, 16(7), 767–771. doi:10.1002/ejhf.106. 11. Lazarevic´, A. M., Nakatani, S., Neskovic´, A. N., Marinkovic´, J., Yasumura, Y., Stojicic´, D., et al. (2000). Early changes in left ventricular function in chronic asymptomatic alcoholics: Relation to the duration of heavy drinking. Journal of the American College of Cardiology, 35, 1599–1606. 12. Cameli, M., Lisi, M., Mondillo, S., Padeletti, M., Ballo, P., Tsioulpas, C., et al. (2010). Left atrial longitudinal strain by speckle tracking echocardiography correlates well with left ventricular filling pressures in patients with heart failure. Cardiovascular Ultrasound, 21(8), 14. 13. Galderisi, M., Henein, M. Y., D’hooge, J., Sicari, R., Badano, L. P., Zamorano, J. L., et al. (2011). Recommendations of the European Association of Echocardiography: How to use echoDoppler in clinical trials: Different modalities for different purposes. European Journal of Echocardiography, 12, 339–353. 14. Wakami, K., Ohte, N., Asada, K., Fukuta, H., Goto, T., Mukai, S., et al. (2009). Correlation between left ventricular end-diastolic
123
19.
20.
21.
22.
23.
24.
25.
26.
27.
28. 29.
30.
pressure and peak left atrial wall strain during left ventricular systole. Journal of the American Society of Echocardiography, 22, 847–851. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders-DMS-V (5th ed.). Washington, DC: American Psychiatric Association. Urbano-Marquez, A., Estruch, R., Navarro-Lopez, F., Grau, J. M., Mont, L., & Rubin, E. (1989). The effects of alcoholism on skeletal and cardiac muscle. New England Journal of Medicine, 320, 409–415. Nagueh, S. F., Appleton, C. P., Gillebert, T. C., Marino, P. N., Oh, J. K., Smiseth, O. A., et al. (2009). Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Journal of the American Society of Echocardiography, 22, 107–133. Devereux, R. B., Alonso, D. R., Lutas, E. M., Gottlieb, G. J., Campo, E., Sachs, I., et al. (1986). Echocardiographic assessment of left ventricular hypertrophy: Comparison to necropsy findings. American Journal of Cardiology, 57, 450–458. Pritchett, A. M., Jacobsen, S. J., Mahoney, D. W., Rodeheffer, R. J., Bailey, K. R., & Redfield, M. M. (2003). Left atrial volume as an index of left atrial size: A population-based study. Journal of the American College of Cardiology, 41, 1036–1043. Iacovoni, A., De Maria, R., & Gavazzi, A. (2010). Alcoholic cardiomyopathy. Journal of Cardiovascular Medicine (Hagerstown, Maryland), 11, 884–892. Morris, D. A., Gailani, M., Vaz Pe´rez, A., Blaschke, F., Dietz, R., Haverkamp, W., et al. (2011). Left atrial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. Journal of the American Society of Echocardiography, 24, 651–662. Santos, A. B., Kraigher-Krainer, E., Gupta, D. K., Claggett, B., Zile, M. R., Pieske, B., et al. (2014). Impaired left atrial function in heart failure with preserved ejection fraction. European Journal of Heart Failure. doi:10.1002/ejhf.147. Kocabay, G., Karabay, C. Y., Colak, Y., Oduncu, V., Kalayci, A., Akgun, T., et al. (2014). Left atrial deformation parameters in patients with non-alcoholic fatty liver disease: A 2D speckle tracking imaging study. Clinical science (London), 126(4), 297–304. Todaro, M. C., Choudhuri, I., Belohlavek, M., Jahangir, A., Carerj, S., Oreto, L., et al. (2012). New echocardiographic techniques for evaluation of left atrial mechanics. European Heart Journal Cardiovascular Imaging, 13, 973–984. Mondillo, S., Galderisi, M., Mele, D., Cameli, M., Lomoriello, V. S., Zaca`, V., et al. (2011). Speckle-tracking echocardiography: A new technique for assessing myocardial function. Journal of Ultrasound in Medicine, 30, 71–83. Tan, T. C., Koutsogeorgis, I. D., Grapsa, J., Papadopoulos, C., Katsivas, A., Nihoyannopoulos, P., et al. (2014). Left atrium and the imaging of atrial fibrosis: Catch it if you can! European Journal of Clinical Investigation. doi:10.1111/eci.12305. Singh, K. J., Cohen, B. E., Na, B., Regan, M., Schiller, N. B., & Whooley, M. A. (2013). Alcohol consumption and 5-year change in left atrial volume among patients with coronary heart disease: Results from the Heart and Soul study. Journal of Cardiac Failure, 19, 183–189. Piano, M. R. (2002). Alcoholic cardiomyopathy: Incidence, clinical characteristics, and pathophysiology. Chest, 121, 1638–1650. Mathews, E. C, Jr., Gardin, J. M., Henry, W. L., Del Negro, A. A., Fletcher, R. D., Snow, J. A., et al. (1981). Echocardiographic abnormalities in chronic alcoholics with and without overt congestive heart failure. American Journal of Cardiology, 47, 570–578. Kupari, M., & Koskinen, P. (1993). Relation of left ventricular function to habitual alcohol consumption. American Journal of Cardiology, 72, 1418–1424.
