Hypertension remains the most prevalent chronic disease worldwide. The estimated total number of adults with hypertension in 2000 was approximately one billion and it is projected to increase to 1.56 billion by 2025 . The rise of hypertension is particularly ominous as it increases the risk for heart disease and stroke, the first and third leading causes of death, respectively, in the United States. Therefore, it is important to identify modifiable risk factors of hypertension, including components of the diet, the prevention of hypertension.
Fish and seafood are the major dietary sources of long-chain omega-3 polyunsaturated fatty acid, including eicosapentaenoic acid (EPA, 20 : 5 omega-3) and docosahexaenoic acid (DHA, 22 : 6 omega-3). Quantities of omega-3 fatty acid, vary by the type of fish and are especially rich in fatty fish, such as salmon and mackerel. On the basis of its potential beneficial effects to prevent coronary heart disease (CHD) death [2,3], fish and omega-3 fatty acid, are included among healthy foods recommended by the American Heart Association (AHA), which recommends the consumption of at least two fish meals per week for primary prevention of CHD and 1 g of EPA and DHA per day for secondary prevention of CHD [4,5]. Furthermore, short-term clinical trials [6–10] and a meta-analysis , have reported favorable effects of omega-3 fatty acid, on blood pressure. However, data on long-term omega-3 fatty acid, and fish intake, particularly when considering the types of fish consumed, in association with risk of hypertension in initially healthy subjects are sparse. Therefore, we conducted a prospective study to examine whether the long-term intake of omega-3 fatty acid, or fish is associated with risk of developing hypertension in the Physicians’ Health Study (PHS).
PHS I was a randomized, double-blind, placebo-controlled trial testing the effects of low-dose aspirin and beta-carotene in the primary prevention of CVD and cancer among 22 071 US male physicians starting in 1982 [12,13]. For the current study, we excluded participants with a history of hypertension at baseline (n = 6064) as well as those with missing baseline data for fish or shellfish consumption (n = 489). We also excluded participants with missing information on one fish or shellfish item and specifically responding with ‘rarely/never’ or ‘one to three times per month’ on the other fish questions. The final baseline population for analyses included 12 279 men. Each participant gave written informed consent, and the Brigham and Women's Hospital (Boston, Massachusetts, USA) Institutional Review Board approved the study protocol.
Ascertainment of hypertension, fish and omega-3 fatty acid consumption, and other covariates
All baseline covariates were obtained from self-reports on mailed questionnaires.
Hypertension was ascertained by self-report on annual follow-up questionnaires and confirmed in a subsample through telephone interview. Incident cases of hypertension in PHS met at least one of three criteria: self-report of newly initiated antihypertensive treatment; self-reported SBP at least 140 mmHg; or self-reported DBP at least 90 mmHg. If the date of incident hypertension was missing, it was randomly assigned between the annual questionnaires without then with hypertension. We previously reported high reproducibility of self-reported hypertension among male physician participants of PHS, with 90% of those newly reporting hypertension and 92% of those with no history of hypertension confirmed through telephone interview . Also, a separate validation study done in physicians showed high agreement for self-reported versus measured BP .
Fish intake was assessed from self-reports on the 12-month follow-up questionnaire. The questionnaire asked about the average intake of four types of fish or shellfish: canned tuna fish, dark meat fish (mackerel, salmon, sardines, bluefish, and swordfish, 4–6 oz.), shellfish (shrimp, lobster, or scallops as a main dish), and other fish (4–6 oz.). Seven frequency response categories included rarely or never, one to three times per month, one time per week, two to four times per week, five to six times per week, daily, and at least two times per day. Fish consumption was then converted to servings per week. Individual fish intake was summed for the average daily intake of fish. The daily intake of omega-3 fatty acid was calculated by multiplying the frequency of intake of each fish or shellfish item with the grams of omega-3 fatty acid per serving of that item (0.17 g for other fish, 0.46 g for shellfish, 0.69 g for tuna fish, and 1.37 g for dark fish), then summed for all four items. Omega-3 fatty acid values per serving of each type of fish were obtained from the United States Department of Agriculture food composition tables . Other dietary factors (red meat, vegetable, fruit, and dairy intake) were also reported on the 12-month follow-up questionnaire. Reproducibility and validity of the four questionnaire items on seafood intake were assessed in a study of 127 male healthy physicians aged 45–70 years. The correlation between two administrations of the food frequency questionnaire 1 year apart were 0.54 for canned tuna, 0.63 for dark meat fish, 0.48 for other fish, and 0.67 for shrimp, lobster, or scallops as a main dish .
Other baseline covariates reported on annual questionnaires included age (in years), height and weight (converted to BMI in kg/m2), smoking (never, past, current), vigorous exercise (less than one time per week, one to four times per week, at least five times per week), alcohol use (one time or less per week, two to six times per week, at least one drink per day), history of hypercholesterolemia (yes, no), and history of diabetes (yes, no).
Fish consumption was classified into five categories: rarely or never, less than one serving per week, one serving per week, two to four servings per week, and at least five servings per week. Omega-3 fatty acid consumption was categorized into quintiles. We presented baseline characteristics across categories of fish and omega-3 fatty acid consumption using generalized linear model (GLM) for continuous variables and χ2 tests for categorical variables. Person-time of follow-up was computed from baseline until the first occurrence of hypertension, death, or date of last known contact. We used Cox proportional hazard models to estimate hazard ratios with corresponding 95% confidence intervals (CI) in a sequence of models. The initial model (Model 1) adjusted for age; a second model added randomized aspirin treatment and beta-carotene, life style factors (smoking, multivitamin use, vigorous exercise, alcohol intake), and dietary factors (red meat intake, vegetable intake, fruit intake, dairy intake; Multivariable Model 1). The final model additionally adjusted for metabolic factors (BMI, diabetes, history of hypercholesterolemia; Multivariable Model 2). We tested for linear trends by fitting a continuous variable to which the median value of each category of fish consumption and quintile of omega-3 fatty acid intake was assigned. In secondary analyses, we evaluated separate associations for each kind of fish (tuna canned fish, dark meat fish, shell fish, other fish) with risk of hypertension. Potential effect modification was evaluated in subgroups of BMI (less than 25, ≥25 kg/m2), presence of prehypertension (SBP 120 to <140 mmHg or DBP 80 to <90 mmHg), and history of hypercholesterolemia (yes, no). We performed sensitivity analyses to assess the robustness of our findings by repeating main analyses after re-categorizing fish and omega-3 fatty acid intake; fish consumption of rarely or never, less than one serving per week, one serving per week, and at least two servings per week. All analyses were completed using SAS, version 9.3 (SAS Institute, Cary, North Carolina, USA). All statistical tests were two-sided and P less than 0.05 was considered significant.
The mean age of participants at baseline was 53.0 ± 8.7 years. Baseline characteristics are summarized in Tables 1 and 2 by categories of fish and omega-3 fatty acid intake, respectively. Compared with men in the lowest categories of fish or omega-3 fatty acid intake, men in the highest intake groups were more likely to regularly drink alcohol, consume more fruits and vegetables, and had a higher prevalence of hypercholesterolemia. For fish oil supplement intake, very few men (less than 1.5%) took fish oil supplements at baseline. During a mean follow-up of 15.8 years, 6299 men (51.3%) developed incident hypertension. In various multivariable models controlling for established hypertension risk factors, neither fish nor omega-3 fatty acid consumption was significantly associated with incident hypertension. For fish consumption of none, one two three times per month, and one, two to four, and at least five times per week, the Multivariable Model 2 adjusted hazard ratios [95% confidence interval (CI)] of hypertension were 1.00 (ref), 1.11 (0.92–1.33), 1.04 (0.89–1.21), 1.07 (0.92–1.25), and 1.10 (0.93–1.30), respectively (P trend = 0.29; Table 3). For omega-3 fatty acid intake, the Multivariable Model 2 hazard ratios (95% CI) of hypertension across increasing quintiles were 1.00 (ref), 1.01 (0.93–1.09), 0.98 (0.90–1.06), 1.07 (0.99–1.16), 1.02 (0.94–1.11), respectively (P for trend = 0.34; Table 3). We also found no association between intake of individual types of fish and risk of hypertension (Table 4). The multivariable-adjusted hazard ratio (95% CI) of hypertension for men who consumed a specific fish item more than three times per week compared with those who consumed no fish were 0.95 (0.77–1.16) for canned tuna fish (P for trend more than 0.05), 1.52 (0.93–2.49) for dark meat fish (P for trend more than 0.05), 1.23 (0.75–2.02) for shellfish (P for trend = 0.03), and 0.91 (0.68–1.20) for other fish (P for trend more than 0.05).
Also, there was no evidence of effect modification by baseline blood pressure or history of hypercholesterolemia (both P for interaction more than 0.05) on the association between either fish or omega-3 fatty acid intake and risk of developing hypertension (Supplemental Tables, http://links.lww.com/HJH/B69). We found significant effect modification by BMI (<25, ≥25 kg/m2) for the association between fish intake and risk of hypertension (P for interaction, 0.035); however, this did not extend to omega-3 fatty acid intake (Supplemental Tables, http://links.lww.com/HJH/B69).
Finally, in sensitivity analysis, we repeated the main analyses after re-categorizing fish and omega-3 fatty acid intake. However, results did not differ from our primary findings. Consideration of the widely accepted threshold of fish consumption recommended by the AHA, at least two servings per week for CHD prevention, was not significantly associated with the risk of hypertension (data not shown).
In a large prospective cohort of middle-aged and older men, neither fish nor omega-3 fatty acid intake was associated with the risk of developing hypertension after more than a decade of follow-up. Fish intake of at least two fish meals per week, which is recommended by the AHA, also did not show a significant association with risk of developing hypertension. This lack of association persisted for different types of fish intake. In addition, we found no evidence of effect modification by baseline blood pressure, BMI, or hypercholesterolemia.
To our knowledge, our study is among the first to evaluate the associations of long-term fish and omega-3 fatty acid intake with the risk of hypertension. However, it remains important to carefully interpret our results with our reliance on self-reported fish and omega-3 fatty acid intake by our physician participants, which may represent a major limitation of this study.
In an observational study from NHANES , which followed 5394 normotensive black and white men and women for 10 years, no consistent significant association among each sex and race was found between fish consumption and the risk of hypertension. Yet, what should be noted is the NHANES study used a different definition of hypertension, characterized by SBP at least 160 mmHg or DBP at least 95 mmHg or medication for hypertension. Also, they created four categories of fish intake by combining baseline and follow-up intake of less than one or at least one time/week as assessed at each time point. Therefore, the use of different definition of hypertension and classification of fish intake could lead their results underestimated the association between fish consumption and the risk of hypertension. Also, the CARDIA and observational study from Korea evaluated the association of fish intake and risk of elevated blood pressure, but not risk of hypertension, with no significant association of fish intake and risk of elevated blood pressure [19,20]. A meta-analysis of prospective observational studies also found no significant association of dietary omega-3 fatty acid and fish consumption and risk of elevated blood pressure . However, they revealed inverse association of long-chain omega-3 polyunsaturated fatty acid as biomarker and risk of elevated blood pressure .
Of note, this report and most observational studies have relied upon self-reported diet to evaluate dietary intake of fish or omega-3 fatty acid [18–20], which is considered a less accurate assessment tool than more objective biomarkers.
In contrast, several clinical trials have evaluated the effects of fish and/or omega-3 fatty acid intake on blood pressure. These clinical trials, combined in several meta-analyses, have reported that fish, fish oil, or omega-3 fatty acid intake can reduce blood pressure [6–9,11,22]. Experimental studies also suggest potential mechanisms by which omega-3 fatty acids may lower blood pressure, including favorable effects on the vascular response to angiotensin , improvements in vascular function, and moderation of inflammation . These data demonstrate quite promising blood pressure lowering effects of omega-3 fatty acid, and the AHA guidelines  and the DASH and Mediterranean dietary patterns emphasize fish intake based on this evidence [25,26] as the major dietary source of omega-3 fatty acid for blood pressure reduction.
However, few studies have evaluated the association of fish intake per se with risk of hypertension. In addition, the duration of treatment and follow-up in clinical trials are typically too short to delineate the longer term effects of omega-3 fatty acid or fish intake on blood pressure and incident hypertension. Moreover, in previous meta-analyses showing favorable effects of fish oil or omega-3 fatty acid on blood pressure, the magnitude of blood pressure reduction was modest (an average of 2 mmHg) with even smaller effects among normotensives [6,7,22]. This appears in line with our finding of no association between fish intake and the risk of incident hypertension in our study of PHS participants free of baseline hypertension.
Also, the dose of omega-3 fatty acid consumption should be considered. Results from previous clinical trials and meta-analysis suggested that intake of more than 2000 mg/day of omega-3 fatty acid (EPA and DHA) is necessary to lower BP . However, according to the data from the NHANES, the average omega-3 fatty acid (EPA and DHA) consumption in the United States is only 113 mg/day . The PHS participants in this study consumed comparatively higher amounts of omega-3 fatty acid, but the majority were still extremely lower than 2000 mg/day. Therefore, insufficient omega-3 fatty acid consumption in the PHS could explain the lack of a significant association of omega-3 fatty acid intake and risk of hypertension.
Our study has several strengths, including its large sample size and long duration of follow-up that allows a large number of incident hypertension cases to accrue. Previous data in PHS demonstrate a high confirmation rate of self-reported hypertension, with 90% of those who newly reported hypertension and 92% of those with no history of hypertension confirmed via telephone interview . Nevertheless, this study also has important potential limitations. First, we rely upon self-reports of fish intake and incident hypertension. Moreover, we did not evaluate the cooking method of fish, which could impact the results. For example, fried white fish contains lower amounts of omega-3 fatty acid and higher amounts of other fats, with consumption of fried white fish associated with a higher risk of cardiovascular disease . Also, we did not measure blood concentrations of fatty acid in the present study, which are a more objective measure of fatty acid intake . Any nondifferential misclassification would tend to bias the observed associations toward the null. Second, our sample consists of predominantly Caucasian, highly educated male physicians, possibly limiting the generalizability of our findings to other socioeconomic or ethnic groups and women. Additional studies in diverse populations are needed. Third, residual confounding because of risk factors unavailable in PHS, such as sodium consumption, blood pressure monitoring, preventive care, and genetics may have impacted our findings. However, we have already comprehensively controlled for various established lifestyle, dietary, and metabolic risk factors for hypertension.
In conclusion, neither fish nor omega-3 fatty acid intake was significantly associated with the risk of developing hypertension in a large-scale, long-term cohort of middle-aged and older US men. This lack of association extended to individual kinds of fish consumed. However, our study participants tended not to consume the amount of omega-3 fatty acid needed to lower BP, nor do our results address the role of fish oil supplementation. Furthermore, we only focused on omega-3 fatty acid and did not consider other nutrients in fish that could otherwise explain its associations with blood pressure and hypertension. Fish and omega-3 fatty acid continue to receive attention for their potential effects on CVD and other cardiometabolic outcomes, yet further studies are needed to confirm or refute these findings. As the overall burden of hypertension remains significant in the United States and around the world, interventions with even small improvements in blood pressure can translate into large population gains in morbidity and mortality rates, and reductions in treatment costs.
We are indebted to the participants in the PHS for their outstanding commitments and cooperation and also thank the entire PHS staff.
Funding/support: The Physicians’ Health Study is supported by grants CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Role of the sponsor: The sponsors of the study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Conflicts of interest
There are no conflicts of interest.
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cohort study; epidemiology; fish; hypertension; omega-3 fatty acid; prevention
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