Favourable effects of exercise-based Cardiac Rehabilitation after acute myocardial infarction on left atrial remodeling

International Journal of Cardiology 136 (2009) 300 – 306 www.elsevier.com/locate/ijcard

Favourable effects of exercise-based Cardiac Rehabilitation after acute myocardial infarction on left atrial remodeling Francesco Giallauria a,⁎, Gianluigi Galizia b , Rosa Lucci a , Mariantonietta D'Agostino a , Alessandra Vitelli a , Luigi Maresca a , Francesco Orio c,d , Carlo Vigorito a a

b

Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Cardiac Rehabilitation Unit, University of Naples “Federico II”, Naples, Italy Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Geriatric Unit, University of Naples “Federico II”, Naples, Italy c Endocrinology, Faculty of Exercise Sciences, “Parthenope” University of Naples, Naples, Italy d Department of Molecular and Clinical Endocrinology and Oncology, “Federico II” University of Naples, Naples, Italy Received 28 January 2008; accepted 3 May 2008 Available online 3 August 2008

Abstract Background: Left atrial enlargement is an important predictor of cardiovascular outcomes in patients after acute myocardial infarction. While the favourable effect of exercise exercise-based Cardiac Rehabilitation (CR) on postinfarction LV remodeling has been well documented, those on LA remodeling have yet to be defined. This study investigated the effects of CR on LA remodeling in postinfarction patients with moderate left ventricular (LV) dysfunction. Methods: Sixty postinfarction patients were randomised randomized into two groups, each composed of 30 patients: group T (LVejection fraction (EF) 43.7 ± 4.2%, mean ± SD) entered a 6-month CR program, whereas group C (EF 44.7 ± 4.4%, P = ns) did not. Doppler echocardiography and cardiopulmonary exercise test were performed upon enrolment and at 6-month. Results: At 6-month, trained patients showed a significant (P b 0.001) improvement in peak oxygen consumption (ΔVO2peak = +5.2 ± 2.1 ml/kg/min) and a reduction in LA (ΔLAVMAX = −1.9 ± 3.7 ml/m2) and in LV volumes (ΔLVEDV = −3.6 ± 4.4 ml/m2). At 6-month, untrained patients showed LAVMAX (+3.6 ± 4.4 ml/m2, P b 0.001) and LV dilation (+4.2 ± 5.1 ml/m2, P b 0.001; group T vs. C, P b 0.001); whereas no significant changes in VO2peak were observed. Multiple linear regression analysis showed that age (β = 0.442, P b 0.001), inclusion in the training group (β = −0.599, P b 0.001), E/A ratio (β = −0.210, P = 0.038), LVEDV (β = 0.376, P b 0.001), and LVEF (β = −0.279, P = 0.007) are significant predictors of LA remodeling. Conclusions: Six-month exercise-based CR in postinfarction patients with mild to moderate LV dysfunction induced a favourable LA remodeling. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Left atrial remodeling; Cardiac rehabilitation; Left ventricular remodeling; Cardiopulmonary functional capacity; Cardiopulmonary exercise test; Acute myocardial infarction; Exercise training

1. Introduction ⁎ Corresponding author. Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Cardiac Rehabilitation Unit, “Federico II” University of Naples via S. Pansini 5, 80131 Naples, Italy. Tel./fax: +39 0 81 7462639. E-mail address: [email protected] (F. Giallauria). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.05.026

Left atrium (LA) enlargement, as determined by echocardiography, is an important predictor of cardiovascular outcome [1–4]. LA enlargement is associated with a poor exercise tolerance [5], and is predictive of future stroke, atrial fibrillation, and death [4,6]. Left atrium enlargement also

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implies a poor prognosis in patients with acute myocardial infarction (AMI) [6,7] and cardiomyopathy [8,9], with an additional prognostic value over that provided by other factors such as left ventricular (LV) volumes. Atrial fibrillation complicating AMI has adverse prognostic implications [10] and it is associated to a larger LA size [3]. It has been widely shown that exercise-based Cardiac Rehabilitation (CR) after AMI has beneficial effects on LV remodeling [11–13] and may even reverse this process in some patients with chronic LV dysfunction [14–16]. Exercise-based CR is also associated with reduced mortality in postinfarction patients [17]. Surprisingly, to date, there are no reports on the effects of exercise-based CR on LA remodeling in postinfarction patients. Given the well-recognised prognostic significance of LA enlargement, in this prospective study we assessed the correlation between exercise-based CR and LA remodeling in postinfarction patients. 2. Methods 2.1. Study population From October 2004 to July 2006, 114 consecutive patients immediately after acute ST elevation myocardial infarction (first event) diagnosed according to American College of Cardiology/American Heart Association (ACC/AHA) guidelines [18] were screened for inclusion into the study. Patients with postinfarction residual myocardial ischemia, atrial fibrillation, severe ventricular arrhythmias, atrio-ventricular block, associated valvular disease requiring surgery, pericarditis, and severe renal dysfunction (i.e., creatinineN2.5 mg/dl) were excluded. After exclusions, 60 patients were enrolled into the study protocol. 2.2. Study design This was a prospective randomized study. All 60 patients, after the acute phase, were transferred to our CR Unit where they were followed for few days to ensure clinical stabilization and pharmacological control and where they underwent initial functional evaluation. At hospital discharge, patients were randomly subdivided into two groups (T = training group; C = control group), each composed of 30 patients (Table 1). A common number of assessments was performed at baseline in all 60 patients and was repeated at the 6-month follow-up visit: cardiovascular physical examination, 12lead electrocardiography, cardiopulmonary exercise test (CPX), Doppler echocardiography, blood chemistry, drug compliance control, and serious events assessment. Group T patients were enrolled in a 6-month exercise-based CR program, while Group C patients were discharged with routine instructions to continue physical activity and maintain a correct lifestyle and were seen only at 6-month follow-up. The study was conducted according to the guidelines of the Declaration of Helsinki, and its protocol was approved by

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our institutional ethical committee. The purpose of the protocol was explained to each subject, and written informed consent was obtained from each patient before beginning the study. 2.3. Cardiopulmonary exercise test All patients underwent an incremental CPX on a bicycle ergometer. Before each test, oxygen and carbon dioxide analysers and a flow mass sensor were calibrated by the use of available precision gas mixtures and a 3-L syringe, respectively. To stabilize gas measurements, patients were asked to remain still on the ergometer for at least 3 min before starting exercise. After a 1-minute warm-up period at 0 W workload, a ramp protocol of 15 W/min was started and continued until exhaustion. The pedalling was kept constant at 55 to 65 rpm. A 12-lead electrocardiogram (ECG) was monitored continuously during the test, and cuff blood pressure was manually recorded every 2 min. Respiratory gas exchange measurements were obtained breath-by-breath with the use of a computerized metabolic cart (Vmax 29C, Sensormedics, Yorba Linda, California). VO2peak was recorded as the mean value of VO2 during the last 20 s of the test and expressed in millilitres per kilogram per minute. At the end of cardiopulmonary exercise test, patients were asked to identify the primary reason for stopping. Predicted VO2peak was determined by the use of a sex-, age-, height-, and weight-adjusted and protocol-specific formula [19]. The ventilatory anaerobic threshold (VAT) was detected by 2 experienced reviewers (C.V. and F.G.) by the use of the V-slope method. The VE versus VCO2 relationship was measured by plotting ventilation (VE) against carbon dioxide production (VCO2) obtained every 10 s of exercise (VE / VCO2 slope): both VE and VCO2 were measured in litres per minute. The VE / VCO2 slope was calculated as a linear regression function, excluding the non-linear part of the relationship after the onset of acidotic drive to ventilation [19]. 2.4. Doppler echocardiography Doppler echocardiography (Hewlett Packard Agilent Sonos 5500 phase-array scanner, Andover, MA, USA) was performed a median of 1 day (range 0 to 3 days) after admission in CR Unit and at 6-month follow-up. Data for all echocardiographic studies were collected prospectively, and the parameters of interest were specified a priori. Measurements were obtained at least two times for an average if the rhythm was sinus. Baseline cardiac rhythm was considered sinus if the patient was in sinus rhythm at the time of echocardiography and had no prior history of atrial arrhythmias. Standard views, including the parasternal long-axis, short-axis at the papillary muscle level, and apical 4- and 2chamber views were recorded according to current American Society of Echocardiography guidelines [20]. Single-plane area was evaluated from the four-chamber view of the left atrium at end-ventricular systole, ensuring that there was no foreshortening of the atrium. The area was then planimetered

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Table 1 Baseline demographic, clinical and echocardiographic characteristics of the study patients assigned randomly to group T (trained) or C (untrained controls). Training (n = 30)

Controls (n = 30)

Demographic and clinical characteristics Age (years) Males (n, %) BMI (kg/m2) Antero-septal AMI (n, %) Inferior AMI (n, %) Other AMI locations (n, %) CK-peak (U/L) Thrombolysis (n, %) PTCA (primary) (n, %) PTCA (rescue) (n, %) LVEF (%)

59 ± 3 23 (77) 25.3 ± 3.2 16 (53) 10 (33) 4 (14) 2459 ± 466 23 (76) 7 (24) 23 (76) 43.7 ± 4.2

58 ± 4 24 (80) 25.5 ± 3.5 15 (50) 11 (36) 4 (14) 2398 ± 554 22 (73) 8 (27) 22 (73) 44.7 ± 4.3

Diastolic function Normal Grade 1 Grade 2 Grade 3

9 (30) 10 (33) 8 (27) 3 (10)

8 (27) 12 (40) 8 (27) 2 (6)

16 (53) [8 ± 3] / 16 (53) [20 ± 6]†

16 (53) [8 ± 3] / 16 (53) [18 ± 6]†

23 (76) [13 ± 6] / 23 (76) [16 ± 5]⁎

22 (73) [12 ± 6] / 22 (73) [15 ± 5]⁎

8 (26) [62 ± 23] / 8 (26) [81 ± 26]⁎

8 (26) [56 ± 17] / 8 (26) [75 ± 27]⁎

29 (96) [208 ± 76] / 29 (96) [207 ± 83]

28 (93) [208 ± 79] / 28 (93) [208 ± 84]

23 (76) [32 ± 10] / 23 (76) [33 ± 10]

22 (73) [30 ± 11] / 22 (73) [31 ± 10]

Treatment (baseline/sixth month) Beta blocker (Carvedilol) n (%) [mean dose in mg/day] ACE inhibitor (Enalapril) n (%) [mean dose in mg/day] ARB (Losartan) n (%) [mean dose in mg/day] Anti-platelet agents (Aspirin) n (%) [mean dose in mg/day] Statin (Simvastatin) n (%) [mean dose in mg/day]

⁎P b 0.05, †P b 0.001 vs. respective baseline. ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; BMI, body mass index; CK, creatine kinase; LVEF, left ventricular ejection fraction; PTCA, percutaneous transluminal coronary angioplasty. Diastolic function: see text.

with the inferior LA border defined as the plane of the mitral annulus, excluding the confluence of the pulmonary veins and the LA appendage. On the basis of common clinical practice, non-indexed LA diameter, with 40 mm as the cut-off for normal, was also assessed [2]. Maximal LA volume (LAVMAX), minimum LA volume (LAVMIN) and LA volume at onset of atrial systole (P wave of ECG, LAVP) were measured in all patients with a modified biplane area-length method. This method as well as the Simpson's method of disc had both been well-validated (21,22). Orthogonal apical views, most commonly apical four- and two-chamber views, were obtained for determination of LA area and length (from the middle of the plane of the mitral annulus to the posterior wall). The apical long-axis view was used instead of the two-chamber view if the left atrium in the latter view appeared foreshortened. LA volume was calculated on the basis of the algorithm ([0.85×A1 ×A2] /L); where A1 is the four-chamber LA area, A2 is the two-chamber or apical long long-axis LA area, and L is the average of the two lengths obtained from the orthogonal views) [2,20–22]. To characterize the three phases of left atrial activity, the following variables were calculated: LA passive emptying volume (LAVPE = LAVMAX − LAVP) and

LA passive emptying fraction (LAPEF = LAVPE / LAVMAX) both representing LA conduit function, LA active emptying volume (LAVAE = LAVP − LAVMIN) and LA active emptying fraction (LAAEF = LAVAE /LAVP) to assess LA pump function, LA total emptying volume (LAVTE =LAVMAX − LAVMIN) and LA total emptying fraction (LATEF = LAVTE /LAVMAX) for LA reservoir function. All volumes were corrected for body surface area (BSA). According to the guidelines [20], other echocardiographic parameters, specified a priori, including indexed LV end-diastolic volume (LVEDV) and indexed LV end-systolic volume (LVESV), LV septal and posterior end-diastolic wall thickness, M-mode LV ejection fraction (LVEF) were recorded. Body size variables used for indexing included BSA (m2), body mass index (BMI) (kg/m2), and height (cm). Mitral inflow was assessed with pulsed-wave Doppler echocardiography (before and with Valsalva maneuver) form the apical 4-chamber view [23]. Pulmonary venous flow was recorded with pulsed-wave Doppler with a sample volume placed ≈1 cm into the right upper pulmonary vein. Diastolic filling was categorized as normal (grade 0), impaired relaxation (grade 1), pseudonormal pattern (grade 2), or restrictive (grade 3) by a combination of pulmonary flow patterns [24].

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Table 2 Cardiopulmonary parameters at baseline and after 6-month exercise-based Cardiac Rehabilitation program. Training (n = 30) Baseline VO2peak (ml/kg/min) VO2AT (ml/kg/min) VE/VCO2slope RERpeak Wattmax (W) HRrest (beats/min) HRpeak (beats/min) SBPrest (mm Hg) SBPpeak (mm Hg)

16.5 ± 2.1 12.2 ± 1.4 33.8 ± 4.0 1.14 ± 0.1 98.5 ± 13.5 70.8 ± 4.1 124.6 ± 5.7 122.5 ± 10.9 163.5 ± 7.3

Controls (n = 30) Sixth month 21.7 ± 2.7 15.0 ± 1.8 29.7 ± 3.9 1.16 ± 0.1 123.9 ± 13.3 68.4 ± 3.7 140.5 ± 4.4 117.5 ± 10.5 160.0 ± 6.9

P value b0.001 b0.001 b0.001 0.093 b0.001 0.004 b0.001 0.008 0.046

Baseline

Sixth month

P value

16.4 ± 1.6 12.7 ± 1.3 32.6 ± 3.3 1.13 ± 0.1 100 ± 12.5 71.4 ± 5.1 123.6 ± 5.4 120.4 ± 10.0 162.0 ± 8.8

16.1 ± 2.2⁎⁎ 12.0 ± 1.6⁎⁎ 36.7 ± 2.8⁎⁎ 1.15 ± 0.1 104.0 ± 14.1⁎⁎ 71.6 ± 6.3⁎ 124.3 ± 5.3⁎⁎ 121.8 ± 9.0 160.8 ± 6.6

0.618 0.085 b0.001 0.105 0.228 0.830 0.615 0.410 0.500

⁎P b 0.05, ⁎⁎ P b 0.001 between groups. Abbreviations: VO2peak, peak oxygen consumption; VO2AT, oxygen consumption at anaerobic threshold; VE/VCO2slope, the slope of increase in ventilation over carbon dioxide output; RERpeak, respiratory exchange ratio at peak exercise; Wattmax, maximal workload; HRrest, heart rate at rest; HRpeak, heart rate at peak exercise; SBPrest, systolic blood pressure at rest; SBPpeak, systolic blood pressure at peak exercise.

The Doppler-echocardiographic studies were all performed by the same physician who was blinded to the patient allocation into the study protocol and unaware of the results of CPX. 2.5. Cardiac Rehabilitation Program This was based on an exercise training protocol which was attended by Group T patients on hospital ambulatory-based regimen 3 times/week. Training session, performed under continuous electrocardiographic monitoring, were was supervised by a cardiologist and a graduate nurse. Each session was preceded by a 5-minute warming-up and followed by a 5minute cooling-down. Exercise was performed for 30 min on a bicycle ergometer with the target of 60–70% of the peak oxygen consumption achieved at the initial symptom-limited CPX monitored by a wearable device. Exercise protocol was performed with a gradual increase in exercise workload until the achievement of the predefined target. Other content of the CR program included tailored psychological evaluation and intervention, dietary counseling, risk factors control and secondary prevention, advice on refraining from smoking and maintaining an at least moderate level of leisure time physical activity and in daily physical activities [25]. 2.6. Statistics Descriptive statistics are given in terms of means ± standard deviation or in percentage for nominal variables. Comparisons between groups at randomization were performed by unpaired t test, χ2 of Fischer exact test as required. Differences between the two groups and changes over time within each group (time effect), as well as any interaction (different trends over time between groups) were assessed by two-way repeated measures ANOVA. The bivariate correlations procedure was used to compute Pearson's correlation coefficients with the significance levels. For all subjects, multiple linear regression analysis (stepwise method) was performed with LAVMAX at sixth

month as dependent variable and with baseline data [age, E/A ratio, LVEDV, LVEF and membership in the untreated or the treated group (code 0/1)] as independent variables. P values ≤ 0.05 were considered significant. All statistical analyses were performed using the software package SPSS, version 13.0 (SPSS Inc., Chicago, Illinois, USA). 3. Results All patients completed the study protocol. All investigations were completed under the same conditions and at the same time of the day for both the baseline and follow-up tests. No differences were present among subgroups in type and mean dosage of drugs assumed throughout the study. Beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blocker were titrated to the maximal tolerated dose in each group and no statistically significant differences were observed between groups (Table 1). 3.1. Exercise training program The study period was similar in both T and C groups (187 ± 11 and 184 ± 12 days respectively, P = ns). No adverse events took place during any of training sessions in group T patients. The average exercise intensity was 67.2 ± 5% of initial VO2peak, and averaged 90 ± 18 min (trained) per week of training session. Attendance was 88% in group T patients for the 6-month ET program (57 ± 3 sessions). 3.2. Cardiopulmonary parameters There were no significant differences between the two groups in baseline hemodynamic and cardiopulmonary parameters (Table 2). After 6-month exercise-based CR, in group T we observed a significant improvement in cardiopulmonary parameters (Table 2). After 6-month exercisebased CR, cardiopulmonary parameters were improved in group T compared to group C patients (Table 2).

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Table 3 Doppler-echocardiography parameters at baseline and after 6-month exercise-based Cardiac Rehabilitation program. Training (n = 30) Baseline LVEF (%) LVEDV (ml/m2) LVESV (ml/m2) M-mode LA dimension (mm) LAVP (ml/m2) LAVMIN (ml/m2) LAVMAX (ml/m2) LAVPE (ml/m2) LAVAE (ml/m2) LAVTE (ml/m2) LAPEF (%) LAAEF (%) LATEF (%) Peak E-wave velocity (cm/s) Peak A-wave velocity (cm/s) E/A ratio E-deceleration time (ms) Pulmonary vein S velocity (m/s) Pulmonary vein D velocity (m/s) Pulmonary vein S/D ratio Rehabilitation Program

43.7 ± 4.2 94.3 ± 10.4 53.0 ± 5.6 39.3 ± 2.7 13.5 ± 3.0 6.8 ± 1.6 20.3 ± 2.5 6.6 ± 3.1 6.8 ± 2.6 13.0 ± 3.3 0.39 ± 0.1 0.44 ± 0.1 0.65 ± 0.1 59.0 ± 7.3 61.8 ± 8.6 0.96 ± 0.1 208.0 ± 30.5 0.5 ± 0.3 0.5 ± 0.3 1.1 ± 0.3

Controls (n = 30) Sixth month 46.2 ± 4.4 90.6 ± 11.7 48.8 ± 7.3 37.6 ± 2.8 12.0 ± 2.2 5.4 ± 1.7 18.4 ± 2.9 8.2 ± 2.4 5.9 ± 2.0 11.8 ± 3.0 0.46 ± 0.1 0.40 ± 0.1 0.66 ± 0.2 64.3 ± 5.9 53.4 ± 6.1 1.22 ± 0.2 196.3 ± 29.6 0.5 ± 0.2 0.5 ± 0.3 1.3 ± 0.3

P value b0.001 b0.001 b0.001 0.002 b0.001 b0.001 b0.001 0.005 0.003 0.009 0.002 0.028 0.669 b0.001 b0.001 b0.001 0.047 0.774 0.821 0.004

Baseline

Sixth month

P value

44.7 ± 4.4 94.9 ± 7.3 52.4 ± 5.5 38.9 ± 2.2 13.3 ± 4.2 6.6 ± 2.0 19.2 ± 3.7 6.4 ± 2.4 6.7 ± 2.8 12.8 ± 4.7 0.38 ± 0.1 0.43 ± 0.1 0.66 ± 0.1 58.8 ± 5.9 60.9 ± 7.4 0.97 ± 0.1 205.6 ± 35.3 0.5 ± 0.3 0.5 ± 0.3 1.1 ± 0.3

42.2 ± 4.5⁎ 98.9 ± 9.3⁎ 57.1 ± 6.5⁎⁎ 41.9 ± 2.9⁎⁎ 18.8 ± 4.0⁎⁎ 9.3 ± 1.8⁎⁎ 22.8 ± 2.7⁎⁎ 4.4 ± 1.9⁎⁎ 10.3 ± 3.4⁎⁎ 16.7 ± 4.5⁎⁎ 0.32 ± 0.1⁎⁎ 0.48 ± 0.1⁎⁎ 0.64 ± 0.2 57.3 ± 6.5⁎⁎ 60.0 ± 5.2⁎⁎ 0.96 ± 0.1⁎⁎ 226.1 ± 39.9⁎ 0.5 ± 0.3 0.5 ± 0.3 1.0 ± 0.2⁎⁎

b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 0.001 0.002 0.443 0.259 0.583 0.700 0.001 0.802 0.865 0.732

P b 0.01, ⁎⁎P b 0.001 between groups. Abbreviations: LAAEF, active emptying fraction; LA, left atrial; LAVP, left atrial volume at the onset of atrial systole, LVEDV, indexed left ventricular enddiastolic volume; LVEF, left ventricular ejection fraction; LVESV, indexed left ventricular end-systolic volume index; LAPEF, passive emptying fraction; LATEF, total emptying fraction; VAE, active emptying volume; VTE, total emptying volume; VMAX, maximal volume; VMIN, minimal volume; VPE, passive emptying volume.

No statistically significant differences were found in baseline Doppler-echocardiographic parameters between group T and C patients (Table 3). At 6-month follow-up, group T patients showed a significant (P b 0.001) decrease in LV volumes, and a significant increase in LVEF (P b 0.001), whereas group C patients showed a significant (P b 0.001) increase in LV volumes and a significant (P b 0.001) decrease in LVEF (P b 0.001 vs. group T) (Table 3).

During the study period, LA volumes significantly (P b 0.05) decreased in group T but increased in group C patients (P b 0.05 vs. group T) (Table 3). At 6-month follow-up, E wave and E/A ratio significantly (P b 0.05) increased in group T but remained unchanged in group C (P b 0.05 vs. group T) (Table 3). In group T patients, we observed a significant correlation between 6-month LA volume and LVEDV changes (r = 0.481, P b 0.01) (Fig. 1); and between 6-month LA volume and E/A ratio changes (r = − 0.389, P b 0.05) (Fig. 2).

Fig. 1. Relationship between changes in maximal left atrial volume (LAVMAX, ml/m2) and changes in left ventricular end-diastolic volume (LVEDV, ml/m2) in trained patients.

Fig. 2. Relationship between changes in maximal left atrial volume (LAVMAX, ml/m2) and E/A ratio in trained patients.

3.3. Doppler-echocardiographic parameters

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Multiple linear regression analysis showed that age (β = 0.442, P b 0.001), inclusion in training group (β = −0.599, P b 0.001), E/A ratio (β = − 0.210, P = 0.038), LVEDV (β = 0.376, P b 0.001), and LVEF (β = −0.279, P = 0.007) are significant predictors of LA remodeling. 4. Discussion The present study shows that 6-month exercise-based CR started early after AMI in patients with mild to moderate LV systolic dysfunction induced a combined reverse LA and LV remodeling correlated with a significant improvement in exercise functional capacity, LVEF and early LV diastolic filling. Left atrial volume is a sensitive marker of future risk of cardiovascular events. Dilatation of the LA, in the absence of organic mitral valve disease or history of atrial fibrillation, has been shown to reflect the burden of cardiovascular disease [2–4,26]. During ventricular diastole, LA is exposed to LV pressure. With increased stiffness of the LV, LA pressure rises to maintain adequate LV filling, and the increased atrial wall tension leads to chamber dilatation and stretch of the atrial myocardium. LA size is, therefore, largely determined by the same factors that influence diastolic LV filling [27,28], thus representing a valid marker of the duration and severity of diastolic dysfunction [29]. Mounting evidence suggests a prognostic role for LA volume to predict the occurrence of chronic heart failure [30,31]. Because the majority of chronic heart failure patients with LV dysfunction are in a preclinical phase of the disease [32], reducing the risk of progression to symptomatic heart failure would be clinically useful. Conversely, in non non-training patients, 6 months after AMI we observed unfavourable LA and LV remodeling, worsening of LVEF and no changes in cardiac functional capacity and early LV diastolic filling. Thus, the present study shows that there is a strong direct relationship between the remodeling of the two cardiac chambers (Fig. 1). Since drugs were equally administered in the two groups, the anti-remodeling effect of exercise training is on top of the recognised favourable effect of several drugs on LA volume changes [33–35]. The present study also confirmed the favourable effects of exercise-based CR on LV remodeling and function showed in previous studies in patients with previous AMI or CHF and more severe compromise of LV systolic function [11–15], and in postinfarction patients with only mild to moderate LV dysfunction [16]. An exercise-induced decrease in LV stress is the most likely explanation of the combined long-term decrease of LA/ LV volumes. In fact, in our training patients we observed an increase in Doppler-echocardiography E wave and E/A ratio, a reflection of a reduced LV afterload and stress [36]. It is well known that Doppler-echocardiographic assessment of instantaneous filling pressure is better suited for monitoring hemodynamic status in the short-term, whereas LA volume is

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useful for monitoring long-term hemodynamic control [28]. Therefore, LA volume measurement may provide an additional diagnostic and prognostic information in these patients. Favourable exercise-induced LA remodeling may represent an additional explanation for the exercise-mediated reduction of cardiovascular events [17], suggesting a possible role of LA size in the reduction of long-term cardiovascular risk after AMI. Obviously, larger prospective studies are required in order to clarify whether the measurement of LA may add new additional information to the evaluation of the effects of CR in postinfarction patients, particularly for those cardiovascular events specifically correlated to LA size (i.e. atrial fibrillation, stroke). 4.1. Study limitations The present study involved relatively young patients (mean age 58 years), predominantly men, with mild to moderate systolic LV dysfunction. Thus, the results may not be applicable to elderly patients or to patients with more severe compromise of LV systolic function. In addition, the present study did not have the power to evaluate the long-term beneficial effects of LA remodeling on clinical grounds. 4.2. Conclusions This study is the first showing the favourable effect of exercise-based CR on LA volume in postinfarction patients. It provides additional information to encourage the inclusion of postinfarction patients in CR programs, aiming at reducing the risk associated to both unfavourable LA and LV remodeling. LA volume is a possible additional tool for improving risk stratification and a marker for evaluation of therapeutic interventions in postinfarction patients. Since a dilated LA is associated with a number of adverse events after AMI, further studies are suggested in order to clarify whether exercise-induced LA size reduction translates into improved outcomes in postinfarction patients. References [1] Bozkurt E, Arslan S, Acikel M, et al. Left atrial remodeling in acute anterior myocardial infarction. Echocardiography 2007;24: 243–51. [2] Tsang TS, Abharayatna WP, Barnes ME, et al. Prediction of cardiovascular outcomes with left atrial size. J Am Coll Cardiol 2006;47:1018–23. [3] Casaclang-Verzosa G, Gersh BJ, Tsang TS. Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol 2008;51:1–11. [4] Benjamin EJ, D'Agostino RB, Belanger AJ, et al. Left atrial size and the risk of stroke and death. The Framingham Heart Study. Circulation 1995;92:835–41. [5] Triposkiadis F, Trikas A, Pitsavos C, et al. Relation of exercise capacity in dilated cardiomyopathy to left atrial size and systolic function. Am J Cardiol 1992;70:825–7.

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