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Heart Disease: pioglitazone & fish
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FISH REDUCED CONGESTIVE HEART FAILURE
"......Among these older adults, consumption of tuna or other broiled or baked fish (not fried fish) was associated with a lower incidence of CHF, with -20% lower a risk with intake 1 to 2 times/week and -30% lower risk with intake ≥3 times/week, compared with intake <1 time/month. Estimated intake of marine n-3 fatty acids was also associated with lower CHF risk, with 37% lower risk in the highest quintile of intake compared with the lowest......"
PIOGLITAZONE IMPROVES CARDIOVASCULAR RISK FACTORS BY ANTI-INFLAMMATORY AFFECT
"......This prospective randomized controlled trial demonstrates significant improvements of multiple cardiovascular risk markers during treatment with pioglitazone in comparison to glimepiride administration over six months. Because metabolic control, as indicated by HbA1c values, was comparably improved in both treatment arms, the observed beneficial effects of pioglitazone on cardiovascular risk markers are suggested to be independent from overall metabolic improvement but may rather be direct effects of PPAR{gamma} activation. This hypothesis is supported by the fact that the observed changes were equally seen in therapy responders and nonresponders....
.....In comparison to glimepiride, pioglitazone treatment led to a significant increase in HDL cholesterol and adiponectin, decrease in fasting glucose and insulin, significant higher reduction of triglycerides, and a significant higher reduction in the LDL/HDL ratio. These pronounced differences between pioglitazone and sulfonylurea treatment have been consistently described by several groups in the literature.... In conclusion, the presented study gives evidence of an anti-inflammatory and potential antiatherogenic effect of pioglitazone that is indicated by improvements in several traditional and nontraditional cardiovascular risk markers and carotid IMT, independent of an improvement in long-term glycemic control...."
YOU CAN READ EXCERPTS FROM BOTH STUDIES (Journal of the American College of Cardiology) BELOW FOLLOWING THIS NOTE FROM FOX NEWS
Diabetes Drugs May Help Fight Inflammation
Fox News
Tuesday, June 21, 2005
By Salynn Boyles
There is growing evidence that a specific class of diabetes drugs may help fight heart disease by also fighting inflammation.
In recent years research has pointed to inflammation as a possible cause of heart disease. And early studies have hinted that the type 2 diabetes drugs Actos and Avandia may help fight heart disease not only by improving blood sugar but also by battling inflammation.
Actos and Avandia belong to the relatively new class of drugs known as thiazolidinediones, or TZDs. They improve blood sugar by reducing insulin resistance, a hallmark of type 2 diabetes. This occurs when the body does not respond as well to the blood-sugar-lowering effects of the hormone insulin.
In a newly published study, researchers compared Actos with an older type of diabetes drug that lowers blood sugar in an entirely different way and does not reduce insulin resistance.
Provocative Information
The studies included results of 173 patients who took either Actos or Amaryl for six months.
Both drugs worked equally well to control blood sugar. But Actos also improved several heart disease risk factors, including cholesterol and markers of inflammation, such as C-reactive protein.
Carotid artery wall thickness, a measure of arteries that supply the brain and an indicator of heart disease, also improved with Actos.
These benefits were not seen in the patients who took Amaryl.
The research was funded by Actos manufacturer Takeda Pharma, and is published in the June 21 issue of the Journal of the American College of Cardiology.
"This is one more bit of provocative information suggesting that TZDs may be a very useful class of drugs for preventing heart disease," American Diabetes Association (ADA) president Robert Rizza, MD, tells WebMD.
"We won't know for sure, though, until we see the results from ongoing studies examining the question."
Heart Disease, Stroke Leading Causes of Death
Heart disease and stroke are the leading causes of death among people with diabetes, with two out of three diabetes patients eventually dying from one of these conditions.
According to one the new study's researchers, it makes sense that the TZDs would protect against heart attack and stroke because insulin is active in the lining of the blood vessels. The drugs' insulin-resistance properties may help reduce inflammation within the lining of the vessels. And less inflammation may mean less heart disease and stroke.
But Andreas Pfutzner, MD, PhD, agrees that larger clinical trials are needed to clarify the true significance of the findings.
Concerns and a Troubled Past
Because Actos and Avandia can cause fluid retention, they are not recommended for people with moderate to severe heart failure.
In a study reported in September of 2003, University of Texas researchers identified six cases of congestive heart failureamong diabetes patients taking the drugs. They concluded that people with diabetes who have mild heart disease or any problems with their kidneys could be at greater risk of developing heart failure if they take Actos or Avandia.
And the first TZD, sold as Rezulin, was blamed for roughly 60 deaths from liver failure and was taken off the market in the spring of 2000. Some critics have expressed similar concerns about the two remaining TZDs, but they are widely considered to be safe alternatives to Rezulin.
CLINICAL RESEARCH: CLINICAL TRIAL
Journal of the American College of Cardiology, June 21, 2005
Improvement of Cardiovascular Risk Markers by Pioglitazone Is Independent From Glycemic Control
Results From the Pioneer Study
OBJECTIVES: This study was performed to assess whether the anti-inflammatory and antiatherogenic effects of pioglitazone suggested by animal experiments are reproducible in man and independent from improvements in metabolic control.
BACKGROUND: Type 2 diabetes is associated with increased cardiovascular risk.
METHODS: A total of 192 patients were enrolled into a six-month, prospective, open-label, controlled clinical study. They were randomized to receive either pioglitazone (45 mg) or glimepiride (1 to 6 mg, with the intent to optimize therapy). Biochemical and clinical markers to assess therapeutic effects included HbA1c, fasting glucose, insulin, adiponectin, lipids, high-sensitivity C-reactive protein (hsCRP), intracellular adhesion molecule, vascular cell adhesion molecule, vascular endothelial growth factor, fibrinogen, von Willebrand factor, matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1, soluble CD40 ligand, and carotid intima-media thickness (IMT).
RESULTS: The study was completed by 173 patients (66 female, 107 male; age [+ SD]: 63+8 years; disease duration: 7.2+7.2 years; HbA1c: 7.5+0.9%; pioglitazone arm: 89 patients). A comparable reduction in HbA1c was seen in both groups (p < 0.001). In the pioglitazone group, reductions were observed for glucose (p < 0.001 vs. glimepiride group at end point), insulin (p < 0.001), low-density lipoprotein/high-density lipoprotein ratio (p < 0.001), hsCRP (p < 0.05), MMP-9 (p < 0.05), MCP-1 (p < 0.05), and carotid IMT (p < 0.001), and an increase was seen in high-density lipoprotein (p < 0.001) and adiponectin (p < 0.001). Spearman ranks analysis revealed only one correlation between the reduction in cardiovascular risk parameters and the improvement in the metabolic parameters (MMP-9 and fasting blood glucose, p < 0.05)
CONCLUSIONS: This prospective study gives evidence of an anti-inflammatory and antiatherogenic effect of pioglitazone versus glimepiride. This effect is independent from blood glucose control and may be attributed to peroxisome proliferator-activated receptor gamma activation.
AUTHOR DISCUSSION
This prospective randomized controlled trial demonstrates significant improvements of multiple cardiovascular risk markers during treatment with pioglitazone in comparison to glimepiride administration over six months. Because metabolic control, as indicated by HbA1c values, was comparably improved in both treatment arms, the observed beneficial effects of pioglitazone on cardiovascular risk markers are suggested to be independent from overall metabolic improvement but may rather be direct effects of PPAR{gamma} activation. This hypothesis is supported by the fact that the observed changes were equally seen in therapy responders and nonresponders.
In comparison to glimepiride, pioglitazone treatment led to a significant increase in HDL cholesterol and adiponectin, decrease in fasting glucose and insulin, significant higher reduction of triglycerides, and a significant higher reduction in the LDL/HDL ratio. These pronounced differences between pioglitazone and sulfonylurea treatment have been consistently described by several groups in the literature (23-26). As one explanation for these findings, glyceroneogenesis has been recently identified as a target of TZDs in cultured adipocytes and fat tissues of Wistar rats. The activation of glyceroneogenesis by TZDs occurs mainly in visceral fat, the same fat depot that is specifically implicated in the progression of obesity to type 2 diabetes. The main role of this metabolic pathway is to allow the re-esterification of fatty acids via a futile cycle in adipocytes, thus lowering fatty acid release into the plasma (27).
Inflammation plays an important role in arteriosclerosis, and measurement of hsCRP has become a novel but emerging tool for detecting individuals at high risk for plaque rupture. A randomized placebo-controlled study with different doses of rosiglitazone resulted in a decrease of hsCRP by 26.8% (4 mg) and 21.8% (8 mg) as compared to the placebo group after 26 weeks in a Caucasian study population (28). In another recent study performed in Japanese patients, treatment with 45 mg of pioglitazone significantly reduced hsCRP by about 27% after three months of treatment, while no change occurred in the placebo comparator group. Independence from glucose metabolism was suggested by ANCOVA analysis (29). In our study, baseline values were much higher than in the Japanese study. The decrease in hsCRP by 29% during pioglitazone treatment for the first time compares directly to an equally effective antidiabetic comparator treatment that did not induce any hsCRP change.
Substantial evidence supports a causal role for MCP-1 and its receptor, CCR2, in the recruitment of monocytes from the circulation into atherosclerotic lesions. It has been shown that activation of PPAR by synthetic ligands or components of oxidized LDL reduces monocyte CCR2 expression and blocks chemotaxis mediated by MCP-1 (30). In parallel, activation of PPAR{gamma} by pioglitazone may be responsible for the observed effects in our study. While no human data has been published yet about the influence of pioglitazone on plasma MCP-1 levels, recent animal experiments have indicated and demonstrated the prevention of coronary arteriosclerosis by additional MCP-1-related anti-inflammatory effects (down-regulation of CCR2 in circulating and lesional monocytes) (16,31). In a small study without an active comparator, six weeks of treatment with 4 mg of rosiglitazone resulted in a significant improvement of plasma MCP-1 in diabetic and nondiabetic subjects (17).
While no data have been published about the influence of pioglitazone on plasma MMP-9 yet, two clinical reports describe the treatment effects of rosiglitazone on this marker. In both cases, however, the studies were only placebo-controlled, and significant differences between the treatment and comparator groups in long-term blood glucose control and HbA1c were the consequence of this design. In one study, MMP-9 decreased in a dose-dependent manner by 12.4% (4 mg dose) and 23.4% (8 mg dose) during 26 weeks of therapy as compared to placebo (28). In the other trial, 4 mg of rosiglitazone twice daily led to a significant reduction in MMP-9 by 24.1% (compared to baseline) after 12 weeks (18). In the presented study, however, the 14.5% decrease in MMP-9 under pioglitazone compares to an increase by 2.8% with a glimepiride treatment that results in the same HbA1c improvement.
No significant changes for sCD40L have been detected in our study. Reduction of this risk marker has been independently reported after treatment with rosiglitazone and troglitazone. A reduction of sCD40 by 18.4% after six weeks of treatment with rosiglitazone (4 mg twice a day) in comparison to placebo was reported by Marx et al. (19), and a mean reduction by 29% in a heterogeneous diabetic population was reported after troglitazone treatment for 12 weeks (12). However, in both study groups, the baseline values of sCD40L were about twice as high as in our study population, which may explain our inability to observe any significant differences with regard to this parameter.
No influence of pioglitazone could also be observed on PAI-1 levels. Some authors describe reduction of PAI-1 expression by TZDs (32,33), but others found no effect on PAI-1 expression at all (34). All these observations, however, have been made in vitro. Osman et al. (35) measured PAI-1 in type 2 patients with restenosis treated with rosiglitazone and could not find any changes in their study population (35).
The major clinical finding of this study is a significant reduction of carotid IMT, a strong and well described clinical predictor of cardiovascular risk and stroke (36,37), exclusively in the pioglitazone-treated study population. This finding and the parallel reduction in several biochemical risk markers including hsCRP, MCP-1, MMP-9, and the increase in adiponectin strongly suggest substantial antiarteriosclerotic actions of pioglitazone in vivo independent from metabolic control. While anti-inflammatory and antiarteriosclerotic effects of pioglitazone have been suggested after analysis of animal experiments (31), this is a first comprehensive clinical investigation of these effects in humans.
The answer to the question, whether the surrogate findings described in this study report can be translated into substantial clinical outcome improvements, is currently under investigation in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study with 5,238 patients with type 2 diabetes. The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. The primary end point is the time from randomization to occurrence of a new macrovascular event or death (38).
In conclusion, the presented study gives evidence of an anti-inflammatory and potential antiatherogenic effect of pioglitazone that is indicated by improvements in several traditional and nontraditional cardiovascular risk markers and carotid IMT, independent of an improvement in long-term glycemic control.
INTRODUCTION
Patients with type 2 diabetes mellitus exhibit an increased propensity to develop extensive arteriosclerosis with its sequelae, unstable angina pectoris and acute myocardial infarction (1,2). Over the last years, experimental data have illuminated the role of inflammation in atherogenesis, while clinical studies have shown that this concept of inflammation in arteriosclerosis applies directly to human patients (3). As such, increased serum levels of inflammatory biomarkers of arteriosclerosis, like C-reactive protein, cytokines, like tumor necrosis factor-alpha or interleukin-6, as well as novel markers like monocyte chemoattractant protein (MCP)-1, soluble CD40 ligand (sCD40L), and matrix metalloproteinases (MMP) have been shown to predict cardiovascular risk and seem to reflect the overall burden of vascular disease in patients. Interestingly, some of these markers are elevated in patients with type 2 diabetes and insulin resistance, indicating a pivotal role of inflammation in this metabolic disorder (4-6). Recent data suggest that the release of inflammatory mediators like tumor necrosis factor-alpha and interleukin-6 from the visceral adipose tissue as well as an activation of vascular cells itself contribute to the inflammatory state in these patients with metabolic syndrome. Therefore, enhanced serum levels of sCD40L may reflect endothelial and platelet activation in diabetic subjects, while increased MMP-9 levels suggest the presence of unstable plaques with activated monocytes/macrophages (7-11). Moreover, elevated soluble adhesion molecules like soluble intracellular adhesion molecule (sICAM) and soluble vascular cell adhesion molecule (sVCAM) are markers of endothelial dysfunction in these patients. Given the increased risk of diabetic patients for macrovascular events, therapeutic strategies that limit inflammation in the vessel wall and reduce serum levels of inflammatory surrogate parameters have been considered a promising tool to influence vascular disease in this high-risk population (12,13).
Recent experimental and clinical data suggest that a novel group of antidiabetic agents, thiazolidinediones (TZDs), like pioglitazone and rosiglitazone, may exhibit anti-inflammatory properties in the vessel wall (14,15). These agents act via the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR{gamma}) and, in addition to their metabolic action, have been shown to regulate the expression of various target genes in vascular cells in vitro and in vivo, subsequently limiting inflammatory cell activation and lesion formation during atherogenesis. Furthermore, clinical data suggest that TZDs reduce inflammatory biomarkers of arteriosclerosis, like C-reactive protein or sCD40L, in treated patients, thus potentially modulating their cardiovascular risk (16-19). Still, most of these studies were placebo-controlled and, as such, did not allow the dissection of metabolic from nonmetabolic TZDs' effects, because TZD treatment, compared to placebo, significantly improved glucose metabolism in all of these studies. Therefore, we performed a six-month prospective, randomized, controlled trial to compare the effect of pioglitazone and sulfonylurea treatment on inflammatory biomarkers of arteriosclerosis, attempting to achieve comparable improvement in blood glucose control in both treatment groups.
METHODS
The prospective randomized monocentric study was approved by the responsible ethics committee and was performed in accordance with the Declaration of Helsinki and the guidelines for good clinical practice. All patient examinations were performed at the Clinical Department of the Institute for Clinical Research and Development (IKFE), Mainz, Germany. After written informed consent was obtained, 192 orally treated patients with type 2 diabetes without prior TZD treatment were enrolled into the trial. After randomization, they either received a fixed dose of pioglitazone (45 mg/day) in the morning or glimepiride (1 to 6 mg/day), titrated for optimal glycemic control. Inclusion criteria included an age of 40 to 75 years, HbA1c: 6.6% to 9.9%, absence of significant hepatic or renal disease, absence of congestive heart failure (New York Heart Association functional class II to IV), no cigarette smoking, and no known carotid artery disease. All study measurements were obtained at study entry and after 26+2 weeks. In order to improve metabolic control, individual medical advice was given to every patient throughout the study. In the pioglitazone group, other additional oral antidiabetic therapy was permitted except for metformin, while only TZDs were excluded for additional treatment in the glimepiride group. All blood draws and measurements were performed in the morning after fasting of the patients from midnight onward.
Fish Intake and Risk of Incident Heart Failure
Journal of College of American Cardiology, June 21, 2005
Dariush Mozaffarian, MD, MPH, FACC*,*, Chris L. Bryson, MD, MS{dagger}, Rozenn N. Lemaitre, PhD, MPH{ddagger},, Gregory L. Burke, MD, MSand David S. Siscovick, MD, MPH{ddagger},,||
* Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts
{dagger} Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington
{ddagger} Cardiovascular Health Research Unit, University of Washington, Seattle, Washington
Department of Medicine, University of Washington, Seattle, Washington
Department of Epidemiology, University of Washington, Seattle, Washington
Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Congestive heart failure (CHF) is a growing clinical and public health problem. In the U.S., nearly 5 million individuals have CHF, more than 500,000 new cases are diagnosed yearly, and CHF health care costs exceed $28 billion annually (1). Congestive heart failure is particularly common with advancing age (2) and is the leading cause of hospitalization among adults age ≥65 years (3). Among older adults, CHF incidence is -2% per year (4) and predicts three to six times higher mortality (5). Identification of measures for preventing CHF, particularly among older individuals, is therefore of considerable clinical and public health importance.
In experimental studies, fish oil favorably affects hemodynamics (6), inflammation (7), vascular responses (8-10), and left ventricular (LV) indices (11-17), each of which could reduce risk of CHF. In cross-sectional analyses (18), intake of tuna or other broiled or baked fish is inversely associated with systolic blood pressure, C-reactive protein levels, and carotid intimal medial thickness, whereas fried fish intake is positively associated with systolic blood pressure and carotid intimal medial thickness, all independent risk factors for CHF (4). However, although the relation between fish intake and coronary heart disease risk has been investigated (19), little is known regarding relation of fish intake, or indeed, any dietary factor, with incidence of CHF in humans.
We investigated associations between fish consumption and incidence of CHF in the Cardiovascular Health Study, a population-based cohort study of determinants of cardiovascular disease among adults age ≥65 years. Our hypothesis was that consumption of tuna and other broiled or baked fish, but not fried fish, would be associated with a lower incidence of CHF.
OBJECTIVES: Our aim was to investigate the relation between fish consumption and incidence of congestive heart failure (CHF).
BACKGROUND: The incidence and health burden of CHF are rising, particularly in older persons. Although n-3 fatty acids have effects that could favorably influence risk of CHF, the relation between fish intake and CHF incidence is unknown.
METHODS: Among 4,738 adults age ≥65 years and free of CHF at baseline in 1989-90, usual dietary intake was assessed using a food frequency questionnaire. In a participant subsample, consumption of tuna or other broiled or baked fish, but not fried fish, correlated with plasma phospholipid n-3 fatty acids. Incidence of CHF was prospectively adjudicated.
RESULTS: During 12 years' follow-up, 955 participants developed CHF. In multivariate-adjusted analyses, tuna/other fish consumption was inversely associated with incident CHF, with 20% lower risk with intake 1 to 2 times/week (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.64 to 0.99), 31% lower risk with intake 3 to 4 times/week (HR = 0.69, 95% CI = 0.52 to 0.91), and 32% lower risk with intake ≥5 times/week (HR = 0.68, 95% CI = 0.45 to 1.03), compared with intake <1 time/month (p trend = 0.009). In similar analyses, fried fish consumption was positively associated with incident CHF (p trend = 0.01). Dietary long-chain n-3 fatty acid intake was also inversely associated with CHF (p trend = 0.009), with 37% lower risk in the highest quintile of intake (HR = 0.73, 95% CI = 0.57 to 0.94) compared with the lowest.
CONCLUSIONS: Among older adults, consumption of tuna or other broiled or baked fish, but not fried fish, is associated with lower incidence of CHF. Confirmation in additional studies and evaluation of potential mechanisms is warranted.
AUTHOR DISCUSSION
Among these older adults, consumption of tuna or other broiled or baked fish was associated with a lower incidence of CHF, with -20% lower a risk with intake 1 to 2 times/week and -30% lower risk with intake ≥3 times/week, compared with intake <1 time/month. Estimated intake of marine n-3 fatty acids was also associated with lower CHF risk, with 37% lower risk in the highest quintile of intake compared with the lowest.
Possible mechanisms: tuna/other fish. The inverse relation between tuna/other fish intake and CHF could be due to other healthier lifestyle or socioeconomic characteristics that reduce CHF risk. We adjusted for education, smoking, physical activity, and various other clinical and behavioral risk factors. Further, findings were similar in analyses stratified by education, income, smoking, physical activity, and clinical characteristics and after adjustment for preceding nonfatal myocardial infarction or atrial fibrillation. Nevertheless, the possibility of residual confounding cannot be excluded.
There are plausible biologic mechanisms whereby tuna/other fish intake might reduce the incidence of CHF. In experimental studies, fish oil favorably affects hemodynamic, vascular, and LV indices. In rats, fish oil intake reduces peripheral vascular resistance (8), reduces myocardial oxygen consumption at given workloads (9), increases contractile recovery following ischemia-reperfusion (9), augments LV response to exercise training (10), and reduces LV hypertrophy (11). In nonhuman primates, fish oil lowers resting heart rate, increases LV ejection fraction, and improves myocardial efficiency, possibly related to enhanced diastolic filling (12,13). In humans, fish oil supplementation lowers blood pressure (6), reduces markers of inflammation (7), attenuates vasoconstrictive responses to angiotensin II (14,15), improves arteriolar compliance (16), and improves LV diastolic filling (17). Each of these mechanisms could contribute to a beneficial effect of tuna/other fish intake on the incidence of CHF.
Although these experimental effects were individually demonstrated in humans in short-term trials of fish oil supplementation (3 to 5 g/day), dietary doses (-0.5 g/day) may result in more modest effects that over the long term combine to reduce CHF risk. In bivariate analyses, tuna/other fish intake correlated with plasma phospholipid EPA+DHA and was inversely associated with blood pressure, C-reactive protein, LV mass, and borderline systolic function at baseline. These associations were most pronounced, and CHF risk was lowest, among persons consuming tuna/other fish at least 3 times/week, the equivalent of -500 mg/day EPA+DHA. Conversely, adjustment for these factors only partly attenuated the inverse association between tuna/other fish intake and CHF risk, suggesting that differences in these factors, based upon a single measurement at baseline, do not completely mediate this association.
If tuna/other fish intake reduces the incidence of CHF, effects could be mediated by influences on systolic function, diastolic function, or both. Effects on diastolic function may be particularly relevant in older persons, as nearly two-thirds of older CHF patients have normal systolic function (2). Experimentally observed effects of fish oil on peripheral vascular resistance and LV diastolic filling (8,12-17) are intriguing, suggesting that fatty fish intake could reduce diastolic heart failure. Further investigation of these effects is warranted.
Possible mechanisms: fried fish. The association between fried fish intake and CHF risk appeared partly related to associations with higher risk clinical and lifestyle factors. However, the balance of benefit versus risk of these fish meals may also be unfavorable. Although detailed information on fish species or cooking oils was not available, the lack of correlation with plasma phospholipid n-3 fatty acid levels suggests that these fish meals were mostly lean (white) fish; although frying adds other fatty acids from the frying oil, it does not reduce the absolute n-3 content (29,30). Frying may add oxidation products (30) or, with partially hydrogenated oils, transfatty acids, and frying may also have adverse health effects when oils/fats are used repeatedly for frying (31,32). Thus, if relatively little benefit is present owing to low fish oil content, the net effect may be detrimental. In bivariate analyses in this report, fried fish intake was positively associated with C-reactive protein, LV mass, and borderline systolic function at baseline, each of which predict incident CHF (4). Further investigation is necessary to confirm these observations, determine if they are specific for certain kinds of fish or frying oils, and examine potential mechanisms and alternative explanations. Although it would be premature to conclude that fried fish intake increases the risk of CHF, our findings indicate that intake of such fish meals is unlikely to reduce CHF risk.
Strengths. The prospective cohort design reduces potential bias from recall differences or control-selection bias. The population-based recruitment strategy enhances generalizability. Standardized assessment of a variety of characteristics increases the capacity to adjust for potential confounding factors. Close follow-up, comprehensive review of potential events, and centralized adjudication reduce the potential for missed or misclassified outcomes.
Study limitations. More detailed information on fish species consumed or other preparation methods was not available. Fish intake was assessed at baseline, and consumption may have changed over time; without bias, this would result in underestimation of the relation between fish consumption and CHF risk. Precise quantification of fish intake was limited by the questionnaire response categories; however, individuals reporting greater tuna/other fish consumption had higher plasma phospholipid EPA+DHA levels, indicating reasonably accurate qualitative ranking of fish intake. Standardized assessment of LV function was not available in all participants at time of CHF diagnosis, so systolic versus diastolic heart failure could not be evaluated. Potential risks of fish intake for other health outcomes, such as from mercury contamination (33), were not evaluated. Residual confounding due to unknown or incompletely measured characteristics could not be excluded. Associations were observed in older, predominantly white individuals participating in a cohort study and may not be generalizable to other populations.
Conclusions. Our findings indicate that consumption of tuna and other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of CHF among older adults. To our knowledge, this is the first study to investigate associations between fish intake and risk of CHF, poised to become the leading cardiovascular health burden in coming decades. Just as the notion that dietary influences on coronary heart disease risk are principally related to saturated fat intake is a concept increasingly outdated (34,35), the possibility that dietary habits have important influences on other cardiovascular outcomes appears increasingly tenable. Confirmation of these findings in other studies and continued investigation of possible mechanisms of benefit and risk, with attention to different types of fish meals, is indicated.
RESULTS
Mean participant age was 73 years at baseline. Median fried fish and tuna/other fish consumption were 0.5 and 1.0 servings/week, respectively. Tuna/other fish consumption was associated with younger age, female gender, higher education, and generally a more favorable cardiovascular risk profile, although higher intake was also associated with greater body mass index and higher low-density lipoprotein cholesterol. Tuna/other fish consumption was positively associated with intakes of fruits, vegetables, alcohol, and total energy and inversely associated with saturated fat intake. Fried fish consumption was associated with male gender, non-white race, lower education, a generally less favorable cardiovascular risk profile, and higher intakes of saturated fat, beef/pork, vegetables, and total energy. Associations of these fish meals with risk of CHF were therefore evaluated with and without adjustment for each of these factors.
During 12 years of follow-up, 955 participants (20%) developed incident CHF. Among individuals consuming tuna/other fish ≥3 times/week, incidence of CHF was 19 per 1,000 person-years, compared with 30 per 1,000 person-years among individuals consuming tuna/other fish <1 time/month (p < 0.0001). Among persons consuming fried fish ≥1 time/week, incidence of CHF was 29 per 1,000 person-years, compared with 21 per 1,000 person-years among persons consuming fried fish <1 time/month (p < 0.0001).
In age-adjusted analyses, tuna/other fish consumption was inversely associated with risk of CHF. After multivariate adjustment (Model 1), relative risks (hazards) of CHF were 0.78 (95% CI = 0.63 to 0.97), 0.68 (95% CI = 0.53 to 0.88), and 0.65 (95% CI = 0.44 to 0.97) for tuna/other fish intake 1 to 2 times/week, 3 to 4 times/week, and ≥5 times/week, compared with <1 time/month (p trend = 0.003).
Further adjustment for other behavioral and lifestyle factors (Model 2) had only a small effect on these risk estimates, indicating little evidence for additional confounding by factors beyond those in Model 1. Notably, lower risk was evident with modest intake (1 to 2 times/week). Further, the observed lower risk was similar for intakes of 3 to 4 times/week and ≥5 times/week (with borderline significance in the latter category owing to less person-time and fewer numbers of events).
In contrast, fried fish consumption was positively associated with incidence of CHF. In age-adjusted analyses, intake ≥1 time/week was associated with a 42% higher risk (95% CI = 21% to 67%), compared with intake <1 time/month. Adjustment for other risk factors (Model 1) partly attenuated this higher risk, suggesting that it might have been partly related to differences in these factors. However, even after multivariate adjustments, there was little evidence to suggest that fried fish intake might lower the risk of CHF (Models 1 and 2).
We also evaluated the relation between dietary EPA+DHA and CHF risk. Because our focus was on diet, we excluded the few participants reporting fish oil supplement use at baseline (n = 181). After multivariate adjustment (as in Model 2), EPA+DHA intake was inversely associated with risk of CHF (p trend = 0.009). Compared with the lowest quintile of intake (<92 mg/day), individuals in the highest quintile (>487 mg/day) had a 37% lower risk of CHF (95% CI = 6% to 43%).
We evaluated for potential mediation or confounding by factors that fish intake might directly influence, including systolic blood pressure, diastolic blood pressure, baseline LV systolic function (normal vs. borderline), low-density lipoprotein, high-density lipoprotein, triglycerides, and C-reactive protein. Adjustment for these factors slightly attenuated the relation between fish intake and incident CHF, with relative risks of 0.83 (95% CI = 0.67 to 1.03), 0.72 (95% CI = 0.55 to 0.95), and 0.73 (95% CI = 0.48 to 1.09) for tuna/other fish intake 1 to 2 times/week, 3 to 4 times/week, and ≥5 times/week, compared with <1 time a month (p trend = 0.03), and relative risks of 0.98 (95% CI = 0.84 to 1.14) and 1.30 (95% CI = 1.08 to 1.56) for fried fish intake 1 to 3 times/month and ≥1 time/week, compared with <1 time/month (p trend = 0.02) (other covariates as in Model 2).
We performed stratified analyses to further assess potential confounding or effect modification. There was little evidence that findings varied according to age, gender, education, income, diabetes, smoking, physical activity, prevalent cardiovascular disease, treated hypertension, or systolic blood pressure (p > 0.05 for each interaction; other adjustments as in Model 1), although CIs were broader in each subgroup because of fewer events. For example, the relative risk of incident CHF with tuna/other fish intake ≥3 times/week, compared with <1 time/month, was 0.70 among never-smokers (95% CI = 0.49 to 1.02), 0.71 among former smokers (95% CI = 0.47 to 1.07), and 0.58 among current smokers (95% CI = 0.28 to 1.24) (p interaction = 0.82); 0.75 among individuals with less than a high school education (95% CI = 0.47 to 1.19), 0.48 among individuals with a high school education (95% CI = 0.30 to 0.78), and 0.66 among individuals with more than a high school education (95% CI = 0.43 to 1.02) (p interaction = 0.17); and 0.66 among individuals with an annual income ≥$35,000 (95% CI = 0.34 to 1.30) and 0.72 among individuals with an annual income <$35,000 (95% CI = 0.54 to 0.95) (p interaction = 0.77). Effect modification by fish oil supplementation could not be evaluated given the few individuals taking fish oil (n = 181), but exclusion of these participants had little effect (data not shown). There was little evidence for interaction between tuna/other fish intake and fried fish intake (p interaction = 0.65).
We also assessed the extent to which the relation between fish intake and CHF incidence might be related to associations between fish intake and nonfatal myocardial infarction (18) or atrial fibrillation (28). After adjustment for prevalent or incident myocardial infarction as a time-varying covariate (other adjustments as in Model 1), fish intake was still associated with an incidence of CHF, with 26% lower risk with tuna/other fish intake ≥ times a week (HR = 0.74, 95% CI = 0.57 to 0.95) compared with <1 time/month, and 38% higher risk with fried fish intake ≥1 time/week (HR = 1.38, 95% CI = 1.15 to 1.65), compared with <1 time/month. In similar analyses adjusting for prevalent or incident atrial fibrillation, fish intake was still associated with incidence of CHF, with 34% lower risk with tuna/other fish intake ≥3 times/week (HR = 0.66, 95% CI = 0.51 to 0.86) compared with <1 time/month, and 28% higher risk with fried fish intake ≥1 time/week (HR = 1.28, 95% CI = 1.07 to 1.53) compared with <1 time/month.
Design and population. In 1989 to 1990 and 1992, 5,888 men and women age ≥65 years were randomly selected and enrolled from Medicare eligibility lists in four U.S. communities (20,21). Baseline evaluation included health status, medical history, physical examination, electrocardiography, echocardiography, carotid ultrasonography, pulmonary function testing, and laboratory testing (2,4,5,20-22). We excluded 687 participants enrolled in 1992 (a food frequency questionnaire [FFQ] was not administered in 1992), 105 participants with incomplete data on fish consumption, and 358 participants with baseline CHF (22) or abnormal LV ejection fraction (<45%) (5) (final n = 4,738). Each center's institutional review committee approved the study, and all subjects gave informed consent.
Dietary assessment. A picture-sort FFQ was administered at baseline to assess usual dietary intake of tuna fish, other fish (broiled or baked), and fried fish or fish sandwiches (fried fish burgers) (18,23). For each type, participants reported their usual intake during the past year, with response categories ranging from ≤4 times a year to ≥5 times/week. For most nutrients, the midpoint of each category was used to sum intakes of different items. On the basis of detailed assessments of fish consumption performed in a separate cohort (24) (D. Siscovick, personal communication, October 18, 2004), the median fish intakes for the two highest response categories were calculated to be slightly less than the category midpoint; this had no effect on the relative ranking of participants' fish intakes or the estimates of relative risk among participants, but likely better estimated the absolute fish intake for each participant. We have shown that as a biomarker of fish oil content, plasma phospholipid levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) correlate with intake of tuna fish (Spearman correlation [r] = 0.35, p < 0.01), other fish (r = 0.59, p < 0.001), and combined tuna/other fish (r = 0.55, p < 0.001), but not fried fish (r = 0.04, p = 0.78) (19). Dietary EPA+DHA was calculated from FFQ responses using estimates for each fish serving (3 to 5 oz) (25), including shellfish, and U.S. commercial landings data (26); this estimate correlated with plasma phospholipid EPA+DHA levels (r = 0.52, p < 0.001, n = 65).
Ascertainment of CHF. Potential cases of CHF were identified from annual examinations, six-month phone contacts, and hospitalization discharge summaries. Incident cases were centrally adjudicated using interviews, outpatient records, discharge summaries, history and examination data, and review of relevant diagnostic tests and consultations (4,27). Confirmation of a diagnosis of CHF required each of the following: 1) CHF symptoms (shortness of breath, fatigue, orthopnea, paroxysmal nocturnal dyspnea) and signs (edema, rales, tachycardia, gallop rhythm, displaced apical impulse) or clinical findings (such as on echocardiography, contrast ventriculography, or chest radiography); 2) diagnosis of CHF by a treating physician; and 3) medical therapy for CHF (diuretics and either digitalis or a vasodilator [nitroglycerin, hydralazine, angiotensin-converting enzyme inhibitor]).
Analysis. Kaplan-Meier methods were used to evaluate CHF-free survival. Risk was estimated using Cox proportional hazards (time at risk until first event, death, or latest follow-up through June 30, 2001), with covariates based on clinical interest, associations with incident CHF (4), or associations with exposures/outcomes in the present analysis. The final model included age; gender; race; enrollment site; education; diabetes; body mass index; prevalent coronary heart disease; prevalent stroke/transient ischemic attack; and intakes of tuna/other fish, fried fish, and total calories. A second model was further adjusted for other behavioral and lifestyle factors including smoking; leisure-time physical activity; and intakes of saturated fat, fruits, vegetables, and alcohol. We also evaluated for potential mediation or confounding by levels of systolic blood pressure, diastolic blood pressure, baseline LV systolic function, low-density lipoprotein, high-density lipoprotein, triglycerides, and C-reactive protein. For parsimony in model construction, we excluded from the final models other covariates that did not materially alter relations between fish consumption and CHF risk, including annual income; treated hypertension; exercise intensity; forced expiratory volume in 1 s; carotid intimal medial thickness; atrial fibrillation; M-mode echocardiography-estimated LV mass; use of aspirin, beta-blockers, lipid-lowering medication, fish oil, and estrogen; serum fasting glucose, insulin, creatinine, and fibrinogen; and estimated intakes of total fat, carbohydrates, protein, linolenic acid, fiber, beef/pork, wine, thiamine, and vitamin C. Missing covariate values (typically <1%) were imputed using age, race, gender, diabetes, and prevalent cardiovascular disease; analyses using population medians or excluding missing data were not appreciably different. Tests for trend were evaluated with intake categories entered as ordinal variables. Potential effect modification was assessed using stratified analyses and likelihood-ratio testing (exposure times covariate term). Analyses were performed using Stata 8.0 (D.M.) (Stata Corp., College Station, Texas), with two-tailed alpha = 0.05.
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