Omega3 Fatty Acids Metabolic Enzyme
6.5 STRENGTHS AND LIMITATIONS OF THIS STUDY
The study population in this project was relatively large and we gathered high-quality data, including data about the ECG parameters, which made possible an extensive adjustment for potential confounding factors. This meant that the analyses were more powerful and thus the results are more reliable. The other strengths of this project include the use of serum long-chain omega-3 PUFAs and hair mercury instead of dietary measurements, which both are regarded as established biomarkers for intake (Hodson, Skeaff et al. 2008, Roman, Walsh et al. 2011).
Because serum fatty acids and hair mercury are objective biomarkers for exposure, their use minimize the bias by misclassification that would reduce the associations towards the null. Unfortunately, we did not have access to omega-3 PUFA concentrations in erythrocyte membrane or adipose tissue, which reflect the longer-term dietary intake (Cao, Schwichtenberg et al. 2006). Furthermore, although on average the hair mercury measurements were made 6 years apart, they showed a high correlation (r=0.91); the 4-year correlations in the serum long-chain omega-3 PUFA measurements were more modest, ranging from 0.47 to 0.56. This may reflect biological variability in the serum fatty acids concentrations or differences in the intake of the long-chain omega-3 PUFAs or to laboratory error. In addition, the coefficients of variation in the measurement of the serum long-chain omega-3 PUFA were rather large. However, as these kinds of bias are most likely random, they would again attenuate the true associations. The blood samples were kept frozen at -80°C before analysis, which prevented degradation of the fatty acids.
Potential limitations of this project include the observational study design, so no conclusions can be drawn about causality. Another potential limitation was that the participants were middle-aged and older men from Eastern Finland, so the findings may not be generalizable to other populations or to women.
Furthermore, the average hair mercury concentrations are somewhat higher in the KIHD cohort than have been reported in other study populations (Mozaffarian, Shi et al. 2011, Wennberg, Bergdahl et al. 2010). Therefore, the results of the present project may not be generalizable to study populations with lower average mercury exposures.
Specifically, in Study I, using heart rate-corrected QT- and JT-intervals and excluding participants with prolonged QRS complex likely reduced the inter-individual variability, which improved the sensitivity to detect associations between the fatty acids and hair mercury and ventricular repolarization. In the analyses with incident SCD, the long follow-up time may have attenuated the associations, which were based only on a single exposure assessment at baseline. Moreover, the relatively small number of SCD events may have limited the power to identify statistically significant associations with SCD risk.
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A specific strength of the Study II was using the VO2max, the golden standard for measuring cardiorespiratory fitness (Laukkanen, Kurl et al. 2002), and ECP, which provides information about the differences in cardiovascular resistance and cardiac afterload (Kurl, Laukkanen et al. 2005).
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The following conclusions can be deduced from this population study on the association of serum long-chain omega-3 PUFA levels and hair mercury concentrations with specific parameters of cardiac functions:
1. Higher circulating concentrations of the long-chain omega-3 PUFAs, mainly a marker of fish intake in this study population, were positively associated with ventricular repolarization, as measured by QTc and JTc. In contrast, the hair mercury concentration had no association with these parameters. However, the inverse association between the long-chain omega-3 PUFAs and the risk of SCD was not explained by the prevention of prolonged ventricular repolarization.
2. Higher circulating concentrations of the long-chain omega-3 PUFAs were associated with higher ECP and VO2max. The mercury concentration modestly attenuated these associations. Since low VO2 and low ECP are considered as risk factors for CVD, these results could partially explain how the intake of fish, especially fish with a low mercury content, may reduce the risk of adverse cardiac events.
3. Higher serum long-chain omega-3 PUFA concentrations were inversely associated with HR at rest. However, this kind of beneficial association was not observed with peak HR during exercise and HR recovery after exercise. Since a higher resting HR is a well-known risk factor of CVD, this result could partially explain how long-chain omega-3 PUFAs may reduce the risk of CVD. Moreover, the hair mercury content was associated with a lower peak HR and it only slightly attenuated the associations of the serum long-chain omega-3 PUFAs, therefore consumption of fish with a lower mercury content is recommended.
4. Higher circulating concentrations of the long-chain omega-3 PUFAs were inversely associated with the occurrence of exercise-induced myocardial ischemia among those individuals with a history of CHD, but not among those with no such history. The hair mercury concentration was associated with a higher occurrence of exercise-induced myocardial ischemia. This finding supported the hypothesis that fatty fish, especially fatty fish with a low mercury content, exert a cardioprotective effect.
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In recent years, the provision of adequate and cost-effective care to combat the increasing prevalence of CVD in societies has received growing attention from national and local governments and international organizations, as well as from the general public. It is well-established that dietary factors play an important role in the development and prevention of CVD. With respect to the dietary factors, the seafood-derived long-chain omega-3 PUFAs have been shown to possess cardioprotective properties. This has been the impetus to clarify the biological mechanisms that account for the cardiovascular benefits associated with the intake of the long-chain omega-3 PUFAs.
In this thesis, higher serum concentrations of the long-chain omega-3 PUFAs were beneficially related to some specific parameters of cardiac electrophysiology and performance. However, hair mercury concentration generally attenuated these cardioprotective associations. This thesis reveals new mechanisms to explain the positive associations of long-chain omega-3 PUFAs with specific parameters of cardiac functions (including ECP and its components, peak HR during exercise and HR recovery after exercise, and exercise-induced myocardial ischemia), whereby intakes of long-chain omega-3 PUFAs and fish may lower the risk of CVD and consequently benefit public health. With respect to the prevention of CVD, guidelines should continue to recommend the intake of fatty fish, which are high in long-chain omega-3 polyunsaturated fatty acids but low in methylmercury. Further investigations among women and other populations will be needed to confirm the generalizability of the findings emerging from this thesis. In addition, the cellular mechanisms underlying the associations of the long-chain omega-3 PUFAs and methylmercury with cardiac functions are still not fully known and should be clarified.
The findings of this thesis generally supported the results of observational studies that have mainly demonstrated the cardioprotective properties of fish intake. In contrast, fish oil trials, especially recent ones, have not confirmed these beneficial effects, perhaps due to the low dose of supplementation and the short follow-up time.
Moreover, the subjects in these recent trials had often been receiving state-of-the-art medication, and they may have had high exposure to EPA+DHA already before the trials through higher fish intake or fish oil use, and therefore these trials may have been underpowered to find beneficial effects on CVD outcome. Further studies, among different study populations, are clearly warranted to examine the effect of long-chain omega-3 PUFAs on the risk of CVD.
In addition to long-chain omega-3 PUFAs and methylmercury, fish contain many other beneficial components such as vitamin D, protein, and selenium, as well as
85 other harmful environmental contaminants such as polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, and chlorinated pesticides. Fish contain very low levels of saturated or trans fatty acids. Further studies should be carried out to investigate the independent and joint effects of these other, potentially health-related, components.
All in all, in agreement with the existing recommendations, the consumption of fatty fish, especially fish which are high in long-chain omega-3 polyunsaturated fatty acids but low in methylmercury, is recommended for the prevention of CVD.
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