Left ventricular remodelling in patients with moderate systolic dysfunction after myocardial infarction: favourable effects of exercise training and predictive role of N -terminal pro-brain natriuretic peptide

Abstract

Aims

To investigate the effects of exercise training (ET) on left ventricular (LV) volumes, cardiopulmonary functional capacity and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in postinfarction patients with moderate LV dysfunction.

Methods

Sixty-one postinfarction patients were randomized into two groups: group T [n = 30, LV ejection fraction (EF) 41.6 ± 11.3%, mean ± SD] entered a 6-month ET programme, whereas group C (n = 31, EF 42.0 ± 7.6%, P=NS) did not. NT-proBNP assay, Doppler-echocardiography and cardiopulmonary exercise test were performed upon enrolment and at sixth months.

Results

At sixth months, trained patients showed an improvement in workload (+26%, P<0.001), Vo_2peak (+31%, P<0.001), LV end-diastolic volume index (LVEDVI; −9%, P<0.001), a reduction in NT-proBNP (−71%, P<0.001) and a significant correlation between changes in NT-proBNP and in LVEDVI (r=0.858, P<0.001). Baseline NT-proBNP correlated with changes in LVEDVI in both trained (r=0.673, P<0.001) and untrained (r=0.623, P<0.001) patients. Group C showed unfavourable LVEDVI dilation (+8%, P<0.001; T vs. C group, P<0.001) and a smaller reduction in NT-proBNP (−40%, P<0.001; T vs. C group, P<0.001).

Conclusions

Six month ET induced a favourable LV remodelling and a marked fall in NT-proBNP that could predict LV remodelling in postinfarction patients with moderate LV dysfunction.

Keywords

cardiac rehabilitation cardiopulmonary functional capacity exercise training left ventricular remodelling myocardial infarction NT-proBNP

Introduction

Left ventricular (LV) remodelling after myocardial infarction (MI) is characterized by complex alterations in LV size and shape, continuing long after infarction healing [1], and often marks the transition to congestive heart failure (CHF). Thus it is an important predictor of long-term mortality [2].

Exercise-based cardiac rehabilitation after MI has beneficial effects on cardiovascular functional capacity, quality of life, risk factors modification, and morbidity and mortality [3]. Despite the concern raised that exercise training (ET) in patients with recent MI could negatively affect the evolution of myocardial healing [4], most studies have shown that after recent MI with severe LV dysfunction ET may attenuate LV remodelling [5–8] and may even reverse this process in patients with chronic LV dysfunction [9]. Less well known is the effect of ET on LV remodelling in postinfarction patients with only moderate LV dysfunction.

Brain natriuretic peptide (BNP) and its inactive N-terminal fragment (NT-proBNP), are released from the cardiac ventricles in response to increased LV wall stress owing to regional or global impairment of LV systolic or diastolic function [10]. Both BNP and NT-proBNP are strong predictors of morbidity and mortality in patients with CHF and coronary heart disease [11–13].

Previously, other authors [14–16] demonstrated that among patients not undergoing an ET programme after MI, those with LV remodelling, were identified by elevated plasma levels of BNP or NT-proBNP, both in the early phase after MI and after 6 months. It is, however, uncertain whether the predictive role of NT-proBNP plasma levels is decreased by the participation to ET, as training itself is associated to favourable effect on LV remodelling [5–9]. Furthermore, little is known on the progressive changes in NT-proBNP plasma levels in the 6 months after acute MI and their relationship to changes in LV dimensions in patients undergoing ET. Previous work from our Institution has shown a decrease in NT-proBNP plasma levels with 3 month ET after MI, a time interval too early for observing a LV remodelling [17].

Therefore, the aim of this study was to assess the effects of a 6 month ET programme on LV volumes and function and on NT-proBNP plasma levels in postinfarction patients with moderate LV dysfunction.

Methods

Study population

Eighty-one consecutive patients immediately after acute ST elevation MI were screened for inclusion into the study. We excluded patients with residual myocardial ischemia, severe ventricular arrhythmias, atrio-ventricular block, valvular disease requiring surgery, pericarditis, and severe renal dysfunction (i.e. creatinine > 2.5 mg/dl). The remaining 61 patients were enrolled into the study protocol.

Study design

This was a prospective randomized controlled study. All 61 patients after the acute phase were transferred to our Cardiac Rehabilitation Unit for clinical stabilization, pharmacological control and functional evaluation. At hospital discharge (7 ± 3 days), patients were randomly subdivided into two groups (T = training group; C = control group), respectively composed of 30 (group T) and 31 (group C) patients (Table 1).

At entry and at 6 month follow-up, all patients underwent Doppler-echocardiography and cardiopulmonary exercise test, and completed a questionnaire for evaluation of leisure time physical activity [18]. Due to its superior stability during laboratory procedures compared with BNP, NT-proBNP was assayed, before training and at 6 month follow-up. Group T patients were enroled in a 6 month exercise-based Cardiac Rehabilitation programme, whereas group C patients were discharged with generic instructions to maintaining physical activity and a correct lifestyle, and were seen only at 6 months.

Table 1

Baseline demographic, clinical and angiographic characteristics of the study patients assigned randomly to group T (trained) or C (untrained controls)


	Group T (n=30)	Group C (n=31)

Demographic and clinical characteristics
Age (years)	55.9±3.1	55.1±3.7
Men	22	22
BMI (kg/m²)	25.6±2.4	25.3±2.9
Antero-septal AMI (n, %)	17 (60)	17 (55)
Inferior AMI (n, %)	10 (30)	9 (29)
Other AMI locations (n, %)	3 (10)	5 (16)
CK-peak (U/l)	2852±473	2738±565
Thrombolysis (n, %)	22 (74)	23 (74)
PTCA (primary) (n, %)	8 (26)	8 (26)
PTCA (rescue) (n, %)	22 (74)	23 (74)
LVEF (%)	41.6n±11.3	42.0±7.6
Angiographic characteristics
No. of diseased arteries	1.6±0.7	1.8±0.9
LAD (n)	21	24
RCA (n)	18	20
Cx (n)	13	12
Treatment (baseline/6th month)
Beta-blocker (Carvedilol) n (%) (mean dose in mg/day)	14 (46) (8±4)/14 (46) (19±7)∗∗	15 (48) (7±3)/15 (48) (18±6)∗∗
ACE inhibitor (Enalapril) n (%) (mean dose in mg/day)	22 (73) (13±6)/22 (73) (16±5)∗	22 (71) (12±6)/22 (71) (15±5)∗
ARB (Losartan) n (%) (mean dose in mg/day)	7 (23) (64±24)/7 (23) (85±24)∗	8 (26) (56±17)/8 (26) (75±27)∗
Antiplatelet agents (Aspirin) n (%) (mean dose in mg/day)	28 (93) (209±82)/28 (93) (210±74)	27 (87) (202±78)/27 (87) (214±87)
Statin (Simvastatin) n (%) (mean dose in mg/day)	23 (76) (32±11)/23 (76) (33±10)	22 (71) (29±11)/22 (71) (31±10)

No significant differences were found for any of the comparisons between the two groups. ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; CK, creatine kinase; Cx, circumflex coronary artery; LAD, left anterior descending coronary artery; LVEF, left ventricular ejection fraction; PTCA, percutaneous transluminal coronary angioplasty; RCA, right coronary artery.

∗

P<0.05;

∗∗

P<0.001 vs. respective baseline (time effect within group).

No significant differences were present among groups in type and mean dosage of drugs assumed throughout the study with the exception of β-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blocker, which were titrated to the maximal tolerated dose in each group (Table 1).

All patients completed the study protocol. All investigations were completed under the same conditions for both the baseline and follow-up tests.

The study was conducted according to the guidelines of the Declaration of Helsinki, and its protocol was approved by our institutional ethical committee. The purpose of the protocol was explained and written informed consent was obtained from each patient before inclusion.

Cardiac rehabilitation programme

The ET protocol was attended by group T patients on hospital ambulatory-based regimen three times per week. Training sessions were supervised under continuous electrocardiography monitoring by a cardiologist, a physiotherapist and a graduate nurse. Each session was preceded by a 5-min warming-up and followed by a 5-min cooling-down. Exercise was performed for 30 min on a bicycle ergometer with the target of 60-70% of V O _2peak achieved at the initial symptom-limited cardiopulmonary exercise test. Exercise protocol was performed with a gradual increase in exercise workload until the achievement of the predefined target.

Laboratory measurements

NT-proBNP was determined with a sandwich immuno-assay on an Elecsys 2010 (Roche Diagnostics, Milan, Italy) as previously described [17].

Doppler-echocardiography

All patients underwent Doppler-echocardiographic study (Hewlett Packard Agilent Sonos 5500 phase-array scanner, Andover, Massachusetts, USA) at the beginning and at 6 month follow-up. The physician performing all Doppler-echocardiography studies was unaware of the results of blood sampling and was blinded to the patient allocation into the study protocol.

Cardiopulmonary exercise test

All patients underwent an incremental cardiopulmonary exercise on a bicycle ergometer with a ramp protocol of 15 W/min continued until exhaustion. Respiratory gas exchange measurements were obtained breath-by-breath with use of a computerized metabolic cart (Vmax 29C, Sensormedics, Yorba Linda, California, USA) [19–21]. The physician performing all the cardiopulmonary exercise tests was unaware of the results of blood sampling and was blinded to the patient allocation into the study protocol.

Statistics

Descriptive statistics are given in terms of means ± standard deviation. Comparison between groups for continuous variables were made using t-test. Pearson's correlation coefficient was used to assess the association between changes in NT-proBNP plasma levels and cardiopulmonary and echocardiographic parameters. Multivariate linear regression was used to assess the degree of association between age, sex, body mass index, V O _2peak, baseline NT-proBNP plasma levels and exercise training vs. 6 month LV end-diastolic volume index (LVEDVI) changes. Statistical significance was set at level less than 0.05, for two-tailed probability independent samples. All statistical analyses were performed using the software package SPSS, version 15.0 (SPSS Inc., Chicago, Illinois, USA).

Results

Cardiopulmonary parameters

No significant differences were observed between the two groups in baseline cardiopulmonary parameters (Table 2). After 6 month ET, in group T we observed a significant improvement in V O _2peak, V O _2AT, Watt_max and in resting heart rate and systolic blood pressure, whereas no changes were observed in group C patients. After 6 month ET programme, V O _2peak, V O _2AT and Watt_max were higher in group T compared with group C patients (Table 2).

Doppler-echocardiography parameters and NT-proBNP plasma levels

No differences were found at baseline between group T and C patients in NT-proBNP plasma levels and Doppler-echocardiographic parameters (Table 2). In both groups, ET was associated with a fall in NT-proBNP, but 6 month NT-proBNP plasma levels were higher in group C compared with group T patients. E wave and E/A ratio increased in group T at 6 months, but remained unchanged in group C. LVEDVI and LV end-systolic volume index (LVESVI) decreased in group T, but increased in group C patients. Six month LVEDVI and LVESVI in group T were lower than those in group C (Table 2). A significant correlation existed between 6 month changes in NT-proBNP and in LVEDVI (r = 0.858; P < 0.001) (Fig. 1). Stepwise multivariate linear regression analysis showed that only baseline NT-proBNP plasma levels and ET were significantly associated with 6 month LVEDVI changes (Table 3). At each level of baseline NT-proBNP plasma levels, 6 month LVEDVI changes were lower in group T compared with group C patients (Fig. 2). In group T patients we also observed a significant inverse correlation between 6 month changes in NT-proBNP, V O _2peak (r = −0.556, P < 0.001) and in Doppler-echo E wave (r = −0.435, P<0.001).

Table 2

NT-proBNP plasma levels, cardiopulmonary and Doppler-echocardiography parameters at baseline and after 6 month exercise-based Cardiac Rehabilitation programme


	Group T (trained group) (n=30)		Group C (untrained group) (n=31)

	Baseline	Sixth month	Baseline	Sixth month

NYHA class	2.7±0.7	2.3±0.6‖	2.6±0.5	2.9±0.8 § , †
NT-proBNP (pg/ml)	1306±278	413±302 ¶	1323±281	821±347 ¶ , †
V O _2peak (ml/kg/min)	16.4±1.6	21.4±2.3 ¶	16.3±2.0	16.9±1.3 †
V O _2AT (ml/kg/min)	12.2±1.5	15.2±1.7 ¶	12.5±1.3	11.8±1.5 § , †
VE/V CO _2slope	34.1 ± 4.3	29.7±3.7 ¶	32.9±3.0	36.0±3.1 ¶ , †
RER	1.13±0.06	1.15±0.06	1.12±0.05	1.14±0.04
Watt_max (W)	97.9±12.9	121.5±13.0 ¶	98.1±13.2	99.3±15.2 †
HR_rest (beats/min)	70.8±4.7	68.3±3.6 §	70.0±5.3	71.3±6.2∗
HR_peak (beats/min)	124.9±5.1	140.7±4.6 ¶	122.9±5.4	125.7±8.7 †
SBP_rest (mmHg)	122.0±11.9	118.2±10.0	121.1±10.0	122.2±8.1
SBP_peak (mmHg)	162.8±7.1	159.5±6.3 §	161.4±10.8	159.7±7.7
E wave (cm/s)	59.5±6.2	65.2±6.6 ¶	57.6±7.3	60.0±4.7 †
E/A ratio	0.98±0.1	1.22±0.2 ¶	1.0±0.14	1.0±0.15 †
LVEDVI (ml/m²)	107.3±18.8	97.4±17.9 ¶	105.2±12.1	113.7±12.5 ¶ , †
LVESVI (ml/m²)	60.3±6.9	55.2±11.9 §	59.1±6.4	69.9±10.0 ¶ , †
LVEF (%)	41.6±11.3	42.7±8.3	42.0±7.6	38.2±8.3 ¶ ,∗

A-wave, peak mitral flow velocity during atrial systole; E-wave, peak mitral flow velocity during early filling; HR_peak, heart rate at peak exercise; HR_rest, heart rate at rest; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; NT-proBNP, amino-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association functional class; RER, respiratory exchange ratio; SBP_peak, systolic blood pressure at peak exercise; SBP_rest, systolic blood pressure at rest; V O _2peak, peak oxygen consumption, V O _2AT, oxygen consumption at anaerobic threshold; VE/V CO _2slope, the slope of increase in ventilation over carbon dioxide output; Watt_max, maximal workload.

∗

P<0.05,

^† P< 0.001, interaction;

^§ P<0.05, ‖P<0.01,

^¶ P<0.001, time effect within group.

Exercise training programme and leisure time physical activity questionnaire

The study period was similar in both T and C groups (184±13 and 182±15 days, respectively, P=NS). Clinical events occurred in 22% of patients in the control group and in 10% in the training group (P < 0.05). In the control group, three patients presented worsening dyspnoea thus requiring hospitalization, two patients experienced reinfarction and two patients underwent repeated revascularization. In the exercise group, one patient experienced reinfarction and two patients underwent repeated revascularization. No adverse events took place during any of training sessions in the group T patients. The average exercise intensity was 66 ± 8% of initial V O _2peak, and average time of training session was 90±25 min/week. Attendance was 100% in the group T patients (56±2 sessions). At entry, 70% of group T patients and 74% of group C patients reported no or low LTPA level (P=NS). At 6 month follow-up, 53% of group T patients compared to only 29% of group C patients were involved in moderate or high LTPA level (P<0.001).

Table 3

Multivariate linear regression analysis using 6 month LVEDVI changes as dependent variable


Variable a	Standardized β-coefficients	r ²	P value

Group (training or control)	0.817	0.686	< 0.001
Baseline NT-proBNP plasma levels	0.358	0.814	< 0.001

LVEDVI, left ventricular end-diastolic volume index.

Variable entered in the model: age, sex, body mass index, group, VO_2peak and baseline NT-proBNP plasma levels.

Discussion

This randomized, controlled study shows that a 6 month ET programme in patients with moderate LV dysfunction after acute MI has an antiremodelling effect, whereas in control patients we observed an unfavourable LV remodelling. As drugs were equally administered in the two groups, the antiremodelling effect of ET is on top of the recognized favourable effect of several drugs on LV volume changes after MI [22].

The results of this study amplify the favourable effect of ET on LV remodelling and function after MI shown in previous studies [5–9], extending to postinfarction patients with only moderate LV dysfunction, the antiremodelling effect of ET demonstrated in patients with previous MI or chronic heart failure and more severe compromise of LVEF [9, 23, 24].

The correlation between the fall in NT-proBNP and the change at 6 months in LV volumes found in our study suggests that a ET-induced reduction in LV stress may play a major role in the favourable effects of ET on LV remodelling after MI, although an improvement in sympatho/vagal balance [25] or endothelial function [26], or an increased contractility of hibernating myocardium [27], may also play a role.

An ET-induced decrease in LV stress is also suggested by the increase in Doppler-echocardiography E wave and E/A ratio, and by the significant inverse correlation between changes in NT-proBNP and changes in E wave, as an improved early LV diastolic filling may be a reflection of a reduced LV afterload and stress [28]. E wave and E/A ratio did not change in nonexercising patients, who showed positive LV remodelling and a less pronounced fall in NT-proBNP. A reduction in LV wall stress may be attributed to an ET-induced improvement in arterial endothelial function [26]; one of the main determinants of the improvement in functional capacity observed after ET. This interpretation is supported by the significant correlation found between changes in NT-proBNP and changes in VO_2peak, a parameter expressing maximal cardiac functional capacity, and well correlated to improvement of arterial endothelial function [29].

Our study confirms the ability of NT-proBNP plasma levels measured 10 days after MI in predicting further LV remodelling [14–16]. This study provides the new information that the performance of an ET programme does not reduce the predictive value of NT-proBNP measured few days after MI. In fact, the correlation between NT-proBNP levels and changes in LVEDVI was found both in training and nontraining patients (Fig. 2). Therefore, on the basis of the NT-proBNP plasma levels observed 10 days after MI, it is possible to predict those patients at higher risk of future LV remodelling and therefore of cardiac failure and increased long-term mortality. The beneficial effect of ET on LV remodelling is additional, as at each baseline NT-proBNP level the change in LVEDVI at 6 months in training patients was more favourable than in nontraining patients (Fig. 2). In addition, multivariate analysis confirmed that only ET and baseline NT-proBNP were independent predictors of changes in LVEDVI (Table 3). Therefore, this study provides additional information to encourage the inclusion of postinfarction patients in ET programmes, even with only moderate LV dysfunction, with the aim of reducing the risk associated to unfavourable remodelling.

Finally, this study confirms that a long-term ET programme is associated with improvement in maximal cardiovascular functional capacity [30] and in the intensity of leisure time physical activities [31] in post-infarction patients with moderate LV dysfunction.

As this study involved young patients (mean age 55 years), predominantly men, with moderate LV dysfunction, its results may not be applicable to elderly patients, women or to patients with worse LVEF.

In conclusion, 6 month ETearly after MI in patients with moderate LV systolic dysfunction induces a reverse LV remodelling correlated with a significant reduction in NT-proBNP plasma levels, and an improvement in functional capacity, LVEF and early LV diastolic filling. On the contrary, in nontraining patients, 6 months after MI we observed unfavourable LV remodelling, sustained high values of NT-proBNP, worsening of LVEF and no changes in functional capacity and early LV diastolic filling. The correlation between the fall in NT-proBNP levels and the reduction in LVEDVI and the improvement in early LV diastolic filling in training patients may be a reflection of an ET-induced reduction of LV systolic stress, that may constitute the main pathophysiological basis of reverse LV remodelling in these patients. In addition, NT-proBNP plasma levels obtained short after MI could be predictive of future changes in LV volumes in patients with moderate LV dysfunction after acute MI, both in training and in nontraining patients.

Footnotes

Acknowledgements

Financial support: none. Conflict of interest: none.

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