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European Journal of Heart Failure 2005 7(5):904-909; doi:10.1016/j.ejheart.2005.04.008
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© 2005 European Society of Cardiology

Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids{star}

Alejandro Macchiaa, Giacomo Levantesia, Maria Grazia Franzosic, Enrico Geracid, Aldo Pietro Maggionib, RosaMaria Marfisia, Gian Luigi Nicolosih, Carlo Schweigerg, Luigi Tavazzif, Gianni Tognonia, Franco Valagussae, Roberto Marchiolia,* and on behalf of the GISSI-Prevenzione Investigators

a Consorzio Mario Negri Sud Santa Maria Imbaro, Chieti, Italy
b Centro Studi ANMCO Firenze, Italy
c Department of Cardiovascular Disease Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
d Ospedale Cervello, Palermo, Italy
e Ospedale Civile Presidio di Riabilitazione, Passirana di Rho, Milano, Italy
f IRCCS Policlinico San Matteo, Pavia, Italy
g Ospedale San Gerardo, Monza, Italy
h Ospedale S. Maria degli Angeli, Pordenone, Italy

* Corresponding author. Laboratory of Clinical Epidemiology of Cardiovascular Disease, Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Via Nazionale, 66030 Santa Maria Imbaro, Italy. Tel.: +39 0872 570252; fax: +39 0872 570206. E-mial address: marchioli{at}negrisud.it


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 References
 
Background: Sudden death (SD) has a major impact on mortality (M) in patients with left ventricular systolic dysfunction (SyD). In GISSI-Prevenzione, treatment with n-3 polyunsaturated fatty acids (PUFA) reduced M and SD in post-MI patients, but their effect in patients with SyD is unknown.

Methods: 11,323 patients with prior MI and NYHA class≤II were recruited. After excluding patients with no ejection fraction (EF) measurement (1684), and those with missing data (n=9), 9630 patients were available for analysis. Multivariate Cox regression adjusted models were fitted.

Results: Compared to patients with EF>50%, SyD patients had higher M (12.3% vs. 6.0%) and SD (3.4% vs. 1.4%) rates. PUFA reduced M similarly in patients with (RR 0.76 (0.60–0.96) P=0.02) and without SyD (RR 0.81 (0.59–1.10) P=0.17) (heterogeneity tests P=0.55). In contrast, the effect on SD was markedly asymmetrical: PUFA produced a marked reduction (RR 0.42 (0.26–0.67) P=0.0003) of risk in SyD patients whereas the effect was less evident (RR 0.89 (0.41–1.69) P=0.71) in patients with EF>50% (heterogeneity tests P=0.07). There was a significant increase in SD with worsening EF (P test for trend=0.02), the benefit on SD in patients with EF≤40% being 4-fold higher than in those with EF>50%.

Conclusions: Increasing SyD is associated with elevated risk of SD and with increasing benefit from PUFA. The effect of PUFA on SD reduction was greater in patients with SyD. Prospective trials testing the effect of PUFA in populations with SyD are required.

Key Words: Fatty acids • Unsaturated • Sudden death • Left ventricular systolic dysfunction

Received September 28, 2004; Accepted April 19, 2005


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 References
 
Severe left ventricular systolic dysfunction after myocardial infarction (MI) has a major impact on mortality (M), by increasing progression to overt heart failure as well as sudden death (SD) [1–3]. A number of randomized trials have been carried out in patients with mild to moderate left ventricular systolic dysfunction to evaluate different pharmacological approaches to reduce SD, but, with the exception of beta blockers results were disappointing [4–9]. Although ACE inhibitors [10] and more recently eplerenone [11] have been shown to reduce sudden death in patients with overt CHF, only automatic implantable cardioverter defibrillators (AICDs) have been consistently shown to reduce total mortality and sudden death in the relatively small group of patients with severe impairment of ventricular function [12,13].

Due to the high cost of AICDs, they can only be recommended for a limited subset of patients at very high risk of SD, However, the number of patients at risk is broader and is not confined to those with severe heart failure or to those with previous symptomatic arrhythmia. Therefore it is important to identify and treat effectively and at low-cost, these post-MI patients with mild to moderate impairment of systolic function because of the high number of SD in this large population.

Treatment with n-3 polyunsaturated fatty acids (PUFA) in GISSI-Prevenzione, a large-scale trial in 11,323 patients with recent myocardial infarction, relatively well-preserved cardiac function, and no disabling symptoms (NYHA≤II) significantly decreased total mortality by 20% and sudden death by 45%, these effects being apparent after the first 3–4 months of treatment [14,15]. Since patients with heart failure are at high risk of sudden death due to arrhythmic events, the GISSI-Prevenzione database facilitated a hypothesis generating exercise to assess the relationship between left ventricular systolic function and the risk of sudden death in post-MI patients with left ventricular systolic dysfunction.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Statistical methods
 4. Results
 5. Discussion
 References
 
A detailed description of the study and demographic information of the population has been previously reported [14,15]. Briefly, 11,323 patients with recent (≤3 months, median 16 days) myocardial infarction were enrolled in GISSI-Prevenzione a multicentre, open-label, clinical trial with blinded validation of events and follow-up duration of 3.5 years. The aim of the study was to assess the efficacy of PUFA (1 g daily) and vitamin E (300 mg daily).

Echocardiographic measurement of EF was not centralized and was determined by geometrical assessment of contraction in multiple 2-dimensional views.

For the present analysis, we included only patients with an echocardiographic measurement of ejection fraction (EF) (n=9,639, 85% of the total cohort). We also excluded 9 patients with preserved systolic function because of missing information about their dyspnea status. The final analysis was therefore carried out on 9630 patients (85.0% of the initial cohort).

Sudden death was defined in the protocol as natural death, instantaneous within 1 h of the onset of acute symptoms, and unexpected as to the time and mode of death. It was stipulated that unwitnessed deaths in patients with no known preceding illness other than coronary heart disease had to be classified as sudden cardiac deaths. The validation of clinical events was assured by an ad hoc committee of experts (cardiologists and neurologists) blinded to the patients treatment assignment.

We classified patients into eight categories according to the degree of left ventricular dysfunction (i.e., EF>65%; EF 61% to 65%; EF 56% to 60%; EF 51% to 55%; EF 46% to 50%; EF 41% to 45%; EF 36% to 40%; and EF≤35%). This initial classification was exploratory. We subsequently combined the EF categories into just 4 different classes, in order to achieve a relatively large number of patients within each group.


   3. Statistical methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
4. Results
 5. Discussion
 References
 
Data analyses on the relationship between EF and outcome as well as on the effect of n-3 PUFA treatment were carried out by fitting various multivariable Cox regression models adjusted for the confounding effect of relevant prognostic indicators. The efficacy of n-3 PUFA treatment was assessed according to intention-to-treat and adjusted for interaction between treatments to ensure the full assessment of the independent effects of PUFA. The following confounding variables were included in the multivariable analysis: (A) non-modifiable risk factors: age and sex; (B) complications after myocardial infarction: electrical instability (defined as ≥10 premature ventricular beats per hour, or sustained or repetitive arrhythmias during 24-h Holter monitoring), residual ischemia (angina pectoris class I to IV, according to the Canadian Angina Classification or positive exercise testing); (C) cardiovascular risk factors: smoking habits, history of diabetes mellitus and arterial hypertension, total blood cholesterol, HDL cholesterol, and presence of peripheral vascular disease and (D) treatment related variables: use of antiplatelet agents, ACE inhibitors and beta blockers. We computed {chi}2 tests for trend and heterogeneity as appropriate. The linearity of the effect of left ventricular systolic dysfunction (LVSD) on the outcome was assessed through fitting classes of LVSD as a continuous variable and the heterogeneity of the effect of n-3 PUFA by increasing levels of LVSD by adding n-3 PUFA by LVSD interactim term.

All probability values are 2-sided. All computations were carried out using SAS statistical package (SAS Institute Inc.).


   4. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
5. Discussion
 References
 
The main characteristics of the patients are described in Table 1. Patients with left ventricular systolic dysfunction were older, with a higher prevalence of diabetes mellitus and other vascular risk factors than patients with preserved left ventricular systolic function. As expected, patients with LVSD had a higher prevalence of both myocardial infarction prior to the index event and peripheral vascular disease and were less likely to have undergone a pre-discharge ergometric stress test, due to contraindications. Overall, the prescription rates for ACE inhibitors, antiplatelet agents, and beta blockers were 40.8%, 88.2%, and 41.6%, respectively.


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  		Table 1 Characteristics of patients with and without left ventricular systolic dysfunction (EF>50%) in the GISSI-Prevenzione study

 
Fig. 1 shows the relationship between left ventricular systolic function and prognosis. Compared to patients with EF>50%, those patients with lower EF values had progressively increasing rates of M and SD. The absolute incidence of M and SD increased with the worsening of left ventricular systolic function from 6.0% and 1.4% in patients with EF>50% to 26.6% and 7.8% in patients with severe LVSD (i.e., EF≤35%), respectively (tests for trend p<0.0001 for both outcome measures). In relative terms, however, the proportion of patients dying suddenly increased less steeply, ranging from 23% in patients with EF>50% to 29% in patients with severe LVSD.


Figure 1
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  		Fig. 1 Rates of total mortality and sudden death according to left ventricular systolic function. Ejection fraction (EF)>50%: n=5306, total mortality 6.01%; EF 46% to 50%: n=1873, total mortality 8.44%; EF 41% to 45%: n=1131, total mortality 10.08%; EF≤40%: n=1320, total mortality 19.62%. Hazards ratios for M (95 percent confidence intervals), P values.

 
Left ventricular systolic dysfunction was an independent predictor of total mortality. Compared with patients with preserved systolic function (EF>50%), those with progressive left ventricular impairment had increasing hazard ratios of death: 1.29 (for EF 46% to 50%), 1.39 (for EF 41% to 45%), 2.00 (for EF 36% to 40%), and 3.29 (for EF≤35%). Systolic dysfunction also predicted the risk of sudden death, the hazards ratios (95% confidence interval) ranging from 1.43 (0.97 to 2.09) to 3.82 (2.56 to 5.69) for patients with mild (EF 46% to 50%) and severe (EF≤35%) impairment of left ventricular function, respectively.

Treatment with n-3 PUFA reduced total mortality in patients with and without systolic dysfunction, 24% (–40% to –4%, p=0.02) and 19% (–41% to +10%, p=0.17), respectively (heterogeneity test P=0.55). In contrast, the effect on sudden death reduction was markedly asymmetrical, with a greater effect in patients with LVSD (relative risk reduction 58% [–74% to –33%] p=0.0003) as compared to patients with preserved systolic function (relative risk reduction 11% [–54% to +69%] p=0.71), although the heterogeneity test was not statistically significant (P=0.07).

We performed a more in depth exploration of the effects of treatment with n-3 PUFA on SD in patients with progressively increasing levels of ventricular dysfunction. Because of the relatively low number of patients, we combined two of the categories (EF 36%–40% and EF≤35%) into one (EF≤40%) for this analysis. The effect of n-3 PUFA treatment on SD was related to the degree of systolic dysfunction (test for trend P=0.02) (Fig. 2) with the benefit on SD reduction in patients with EF≤40% being 4-fold higher than in those with EF>50%.


Figure 2
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  		Fig. 2 Effect of n-3 PUFA treatment on total mortality and sudden death in patients with progressive impairment of left ventricular systolic function. Ejection fraction (EF)>50%: no. 5306, total mortality 6.01%; EF 46% to 50%: no. 1873, total mortality 8.44%; EF 41% to 45%: no. 1131, total mortality 10.08%; EF≤40%: no. 1320, total mortality 19.62%. White squares indicate hazard ratio in each subgroup, with square size proportional to number of cases and horizontal lines representing 95% CIs. The combined risk ratios and their 95% CI are indicated by white diamonds.

 
Finally, no heterogeneity in the effects of n-3 PUFA on total mortality was observed in other major subgroups: gender, age (≤70 years vs. >70 years), history of ventricular arrhythmias, treatment with beta blockers or ACE-inhibitors (data not shown).


   5. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
References
 
The main finding of this explorative, hypothesis-generating analysis, is that treatment with PUFA had beneficial effects in patients with and those without LVSD. In patients with systolic dysfunction, PUFA markedly reduced sudden cardiac death, this effect was not only related to the absolute number of events but was also proportional to progressive impairment of left ventricular function, while in patients with preserved left ventricular function PUFA decreased total mortality. In patients with a greater impairment of ejection fraction, PUFA treatment was four times more effective in reducing sudden death, as compared to patients with normal systolic function.

The known lack of precision of echocardiographic methodology [14] may impair the evaluation of small changes in left ventricular ejection fraction in individual patients, but in the statistical analysis of a large number of patients this inaccuracy would determine a non differential misclassification bias leading to a dilution bias toward the null value. Notwithstanding such bias, the concordance between the magnitude of the reduction of SD in patients with progressively worsening left ventricular systolic function and the parallel, progressive increase in SD suggests that the effect of n-3 PUFA treatment could be mediated by antiarrhythmogenic effects [15], thus corroborating the interpretation of the results on the precocity of the onset of benefit [16]. The benefit of n-3 PUFA was independent of treatment with beta blockers and ACE inhibitors, thus making a possible imbalance in the prescription of these drugs an unlikely explanation for our results. A number of experimental [17–20] and epidemiological data [21–28] support the hypothesis that SD can be reduced by n-3 PUFA treatment. The specific antiarrhythmogenic mechanisms, however, have not been defined in detail. It is has been suggested [29], that n-3 PUFA effects seem to be associated with the final common pathway of antiarrhythmogenesis. Regardless of the initiating stimulus, the protective actions seem to involve the hyperpolarization of cell membranes as well as the modulation of the functioning of various ion channels, including the prolongation of the inactivated state of the fast, voltage-dependent inward sodium current INA. In electrophysiological studies, exposure to n-3 PUFA increased the size of the electrical stimulus required to generate an action potential by some 50% and extended the effective refractory period. On the other hand, the effect of treatment with PUFA on total mortality in patients with and without left ventricular systolic dysfunction was homogeneous and consistent with that observed in the whole cohort [15].

The similar benefits of n-3 PUFA on total mortality in patients with and without LVSD suggests that antiarrhythmogenesis may not be the only mechanism of action of n-3 PUFA. N-3 PUFA have a number of pleiotropic effects on atherosclerosis, thrombosis and inflammation, which could reduce the risk of cardiovascular events [30–35]. Thies et al recently found that atherosclerotic plaques readily incorporate n-3 PUFA from fish-oil supplementation, inducing changes that can enhance stability of the plaques [36]. Since vulnerability of the plaque to rupture, rather than the degree of atherosclerosis, is the primary determinant of thrombosis-mediated acute cardiovascular events [37], stability of plaques could help explain the similar reduction in fatal cardiovascular events we found in patients with and without LVSD. On the other hand, when rupture occurs at the site of a vulnerable plaque leading to thrombosis and death of myocardial cells, the cardiomyocytes surrounding the necrotic area are ischemic, partially depolarized, and more prone to arrhythmic phenomena. In such a situation, the administration of n-3 PUFA could hyperpolarize cell membranes, thus contributing to the electrical stabilization of the cardiomyocytes. Accordingly, the benefit of n-3 PUFA treatment could actually be due to synergy between antiarrhythmogenic and anti-inflammatory mechanisms.

The results presented here must be confirmed by testing n-3 PUFA in other populations at high risk for sudden death. This is the case for patients with overt heart failure as well as for high-risk patients in primary care. A large clinical trial is underway to test the effects of n-3 PUFA in heart failure patients [38]. A similar initiative is being tested in the setting of high-risk patients in primary care.

In conclusion, the benefit of n-3 PUFA treatment on sudden death seems to increase in parallel with the worsening of left ventricular systolic function, suggesting an even greater benefit in patients with heart failure, an hypothesis that should be tested prospectively.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 References
 
{star} The names of GISSI-Prevenzione Investigators are reported in Lancet 1999; 354: 447–55. (14). Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 References
 

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J. Gy. Papp, P. Pollesello, A. F. Varro, and A. S. Vegh
Effect of Levosimendan and Milrinone on Regional Myocardial Ischemia/Reperfusion-Induced Arrhythmias in Dogs
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2006; 11(2): 129 - 135.
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