Usefulness of Routine Periodic Fasting to Lower Risk of Coronary Artery Disease in Patients Undergoing Coronary Angiography

Article Outline

• Abstract
• Methods
• Results
• Discussion
• References
• Copyright

Coronary artery disease (CAD) is common and multifactorial. Members of the Church of Jesus Christ of Latter-day Saints (LDS, or Mormons) in Utah may have lower cardiac mortality than other Utahns and the US population. Although the LDS proscription of smoking likely contributes to lower cardiac risk, it is unknown whether other shared behaviors also contribute. This study evaluated potential CAD-associated effects of fasting. Patients (n₁ = 4,629) enrolled in the Intermountain Heart Collaborative Study registry (1994 to 2002) were evaluated for the association of religious preference with CAD diagnosis (≥70% coronary stenosis using angiography) or no CAD (normal coronaries, <10% stenosis). Consequently, another set of patients (n₂ = 448) were surveyed (2004 to 2006) for the association of behavioral factors with CAD, with routine fasting (i.e., abstinence from food and drink) as the primary variable. Secondary survey measures included proscription of alcohol, tea, and coffee; social support; and religious worship patterns. In population 1 (initial), 61% of LDS and 66% of all others had CAD (adjusted [including for smoking] odds ratio [OR] 0.81, p = 0.009). In population 2 (survey), fasting was associated with lower risk of CAD (64% vs 76% CAD; OR 0.55, 95% confidence interval 0.35 to 0.87, p = 0.010), and this remained after adjustment for traditional risk factors (OR 0.46, 95% confidence interval 0.27 to 0.81, p = 0.007). Fasting was also associated with lower diabetes prevalence (p = 0.048). In regression models entering other secondary behavioral measures, fasting remained significant with a similar effect size. In conclusion, not only proscription of tobacco, but also routine periodic fasting was associated with lower risk of CAD.

Utah routinely has among the lowest rates of death from coronary artery disease (CAD) in the United States.¹ Reports from the 1970s suggested that members of the Church of Jesus Christ of Latter-day Saints (LDS; or Mormons) in Utah had lower cardiac mortality than other Utahns² and the general US population.³ This may be caused by the LDS proscription of smoking, but it is unknown whether other behaviors are partially responsible for the lower risk. Additional protective lifestyle behaviors in that population may include routine periodic fasting; proscription of coffee, tea, or alcohol; frequent attendance of worship services; and receiving support from a social network. Although some of these factors have been studied,⁴, ⁵, ⁶, ⁷ routine fasting has not. Fasting 1 day per month is taught in the LDS population from early youth, and its practice often begins as early as the age of 8 years.⁸ Given the potential cardiovascular and antiaging benefits of caloric restriction⁹, ¹⁰, ¹¹, ¹² and the direct effect of fasting on dietary intake over an extended period, it was hypothesized that routine periodic fasting could have a beneficial effect on such processes as glucose metabolism.¹¹, ¹³, ¹⁴ The objective of this study was to evaluate potential CAD-associated effects of fasting and other behaviors beyond smoking abstinence.

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Methods 

The cardiac catheterization registry of the Intermountain Heart Collaborative Study includes patients from hospitals within Utah-based Intermountain Healthcare. CAD presence was determined from a review of angiograms by the attending cardiologist and was recorded in a database based on the Coronary Artery Surgery Study protocol.¹⁵, ¹⁶ Patients had no CAD (all coronary arteries free of disease or <10% stenosis), moderate CAD (most severe lesion 10% to 69% stenosis), or significant CAD (≥1 lesion ≥70% stenosis). This study primarily compared the more discordant diagnoses of significant CAD and no CAD, excluding moderate CAD as indeterminate. This study was approved by the Intermountain Healthcare Urban Central Region Institutional Review Board.

Demographic and health histories were obtained from physicians and hospital records, including age and gender. Smoking was considered present for active smokers or those with a >10 pack-year history. Body mass index (BMI: weight [kg] ÷ height² [m²]) was computed from measured anthropometrics. Histories of diabetes, hyperlipidemia, and hypertension were physician reported from clinical or laboratory findings and current medication use. For laboratory findings, diabetes was defined as blood glucose ≥126 mg/dl; hypertension, as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg; and hyperlipidemia, as total cholesterol ≥200 mg/dl or low-density lipoprotein cholesterol ≥130 mg/dl. Family history of early CAD was considered positive if a first-order relative experienced cardiovascular death, myocardial infarction, or coronary revascularization at age <65 years for women or <55 years for men.

From 1993 to 2002, all patients presenting for coronary angiography were asked their religious preference using a free-text query: “Do you have a religious/spiritual preference? If yes, please list.” A cohort of n₁ = 4,629 patients (27% of total) responded, and differences in CAD based on religious preference were evaluated using chi-square test. Multivariable logistic regression was used to determine covariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Regressions initially used a conditional stepwise approach, and final models used forced variable entry, with covariables including age, gender, hypertension, hyperlipidemia, BMI, diabetes, smoking, and family history. Analyses were performed using SPSS (version 15.0; SPSS Inc., Chicago, Illinois), and 2-tailed p ≤0.05 was nominally significant.

Consequently, a second population was studied to determine which lifestyle behaviors may contribute to the risk difference observed in population 1. From 2004 to 2006, a survey was administered to all patients before angiography to assess adherence to behaviors that may account for health outcome differences (n₂ = 448). From a review of the potentially shared behaviors among those of the LDS faith, the primary hypothesis was developed that routine fasting may be associated with a lower risk of CAD. Because obesity, diabetes, and metabolic syndrome are strong risk factors for CAD,¹¹, ¹⁷ fasting directly influences caloric intake, and the other potentially shared behaviors were unlikely candidates for reducing the risk of CAD. To assess fasting behavior, patients were asked, “Do you routinely abstain from food and drink (i.e., fast) for extended periods of time.”

Beyond smoking, other potentially shared behaviors of LDS patients (Supplemental Table 1) included levels of social support⁷; proscription of tea, coffee, and alcohol¹⁸; weekly observance of a day of rest¹⁹; and attendance of worship services.¹⁹ Questions about alcohol, tea, and coffee use and social support incorporated components of questions from the National Health and Nutrition Examination Survey. The survey was validated by serial administration to 20 subjects at 0, 3, and 30 days, with follow-up interviews. For alcohol, primary modeling compared any use versus none, whereas further evaluation examined 1 to 7 and >7 drinks/week versus none for beer and for liquor, and wine was evaluated as any versus none (almost no patients reported >7 drinks/week). For religious worship and observing a day of rest, frequency of once a month or more was classified as adherence and compared with nonadherence.

Supplemental Table 1. Health survey questions for secondary behavioral measures.

LDS-PROSCRIBED BEVERAGES

Do you drink alcoholic drinks of any kind?

If yes:

In the past 12 months, how many cans or bottles of beer or lite beer did you drink each week?

In the past 12 months, how many glasses or wine, wine coolers, sangria, or champagne did you drink each week?

In the past 12 months, how many drinks of mixed drinks or shots of liquor (such as tequila, gin, vodka, scotch, rum, whiskey, or liqueurs) did you drink each week?

Do you drink tea (any kind)?

If so, about how many cups per week?

Do you drink coffee?

If so, about how many cups per week?

RELIGIOUS OBSERVANCE

How often do you attend worship services?

Two or more times per week

About once a week

About once a month

Less than once a month

Never

Do you observe a day of rest (a day where your daily activities are primarily devoted to activities such as religious worship, meditation, prayer, reading, visiting with others, or such, and wherein your activities do not include your occupation, vigorous work, or exercise/conditioning)?

If yes, how often?

At least once a week

2–3 times per month

Once a month

Seldom

Never

RECEIPT OF SOCIAL SUPPORT

Do you have a family member or friend to whom you can talk about your health?

Do you have a family member or friend to whom you can talk about your personal problems?

Do you have a family member or friend on whom you can rely for financial support or material assitance if needed?

Although not available for all patients, physical activity–related caloric expenditure (kilocalories per week) was calculated based on survey data collected using the Paffenbarger physical activity questionnaire and divided into quintiles for modeling purposes.²⁰ Socioeconomic measures of income and educational attainment were also surveyed (Supplemental Table 2), although only about 68% of patients (n = 306) completed the income question. Education was categorized into 5 groups based on attainment of high school graduation or less, some college or vocational school experience, college graduation, some graduate school or a masters degree, or a doctoral degree. Income was categorized into 3 groups post hoc based on levels of CAD risk as low (<$30,000), intermediate ($30,000 to $69,999), and high income (≥$70,000).

Supplemental Table 2. Survey questions for socioeconomic status.

Education

What is the highest education level you have completed?

Grade: 6 or less, 7, 8, 9, 10, 11, 12 (12=high school graduate)

College: 13, 14, 15, 16 (16=college graduate)

Technical/Vocational: 13, 14 (14=graduated)

Graduate school: 17, 18, 19, 20 (18=masters degree, 20=doctoral degree)

Income

What is your current gross household income per year (that is, your income or the combined income of you and your spouse, and any others who live in your home)?

Less than $10,000

$10,000–$14,999

$15,000–$19,999

$20,000–$29,999

$30,000–$39,999

$40,000–$49,999

$50,000–$69,999

$70,000–$99,999

$100,000 or more

Associations with CAD for fasting and other behaviors were tested using chi-square test or Fisher's exact test, and each metric was subsequently evaluated using multivariable logistic regression. Regression models adjusted for age, gender, smoking, diabetes, hyperlipidemia, hypertension, BMI, and family history of early CAD. Because diabetic patients may be instructed not to fast because of their medical condition, subanalyses of fasting were performed for diabetic and nondiabetic strata. Stratified analyses were also performed according to religious preference and smoking and the other cardiac risk factors. Effect modification on fasting by each other variable was tested using a regression interaction modeled as y = β₀ + β₁ * X₁ + β₂ * X₂ + β₃ * (X₁ * X₂), where y is CAD status, β_i is the ith regression coefficient, X₁ is reported fasting status, and X₂ is 1 of the covariables. For the secondary behavioral measures, additional models were evaluated entering fasting as a covariable to assess confounding.

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Results 

Baseline characteristics were listed in Table 1 for population 1 (n = 4,629) and Table 2 for population 2 (survey population, n = 448). In population 1, a total of 61% of LDS preference patients and 66% of others had CAD (OR 0.81, 95% CI 0.70 to 0.93, p = 0.002), and this was significant after adjustment (OR 0.81, 95% CI 0.69 to 0.95, p = 0.009). A similar effect size was found in population 2 (univariable OR 0.80, 95% CI 0.50 to 1.28, p = 0.35; multivariable OR 0.78, 95% CI 0.45 to 1.35, p = 0.37), although sample size was much smaller.

Table 1. Baseline characteristics for the initial population 1 and for strata defined by religious preference

Characteristic	Overall (n = 4,629)	LDS Preference (n = 3,162)	Other Religious Preference (n = 1,467)	pValue
Age (yrs)	63.6±13.0	64.5±12.8	61.5±13.2	<0.001
Men	64%	63%	65%	0.09
Diabetes mellitus	18%	19%	17%	0.07
Hypertension	51%	52%	50%	0.23
BMI (kg/m2)	28.3±5.8	28.5±5.9	27.9±5.6	0.002
Hyperlipidemia⁎	43%	41%	46%	0.008
Family history of early coronary disease†	29%	29%	29%	0.97
Smoker	18%	12%	31%	<0.0001

Statistical comparisons are of each factor by religious preference.

Table 2. Baseline characteristics in the second (survey) population 2

Characteristic	Overall (n = 448)	Fasting (n = 122)	Nonfasting (n = 326)	pValue	LDS Preference (n = 297)	Other Religious Preference (n = 151)	pValue
Age (yrs)	63.8±11.9	62.8±11.1	64.2±12.1	0.28	64.2±12.1	62.7±11.5	0.23
Men	69%	68%	69%	0.97	66%	73%	0.15
Diabetes mellitus	18%	12%	20%	0.048	20%	13%	0.07
Hypertension	58%	53%	60%	0.17	57%	59%	0.69
BMI (kg/m2)	28.7±6.0	28.1±5.4	28.9±6.3	0.27	28.9±6.2	28.1±5.7	0.25
Hyperlipidemia⁎	57%	62%	56%	0.25	58%	57%	0.87
Family history of early coronary disease†	39%	42%	38%	0.45	39%	39%	0.98
Smoker	13%	3%	17%	<0.001	7%	24%	<0.001
LDS preference	66%	92%	57%	<0.001	—	—	—
Physical activity (caloric expenditure: kcal/wk, n = 330)
Quintile 1	20%	8%	25%		21%	16%
Quintile 2	19%	20%	18%		20%	17%
Quintile 3	22%	18%	25%		21%	25%
Quintile 4	19%	27%	15%		20%	16%
Quintile 5	20%	26%	18%	0.001	18%	26%	0.26
Annual income (n = 306)
<$30,000	30%	21%	33%		32%	25%
$30,000–$69,999	46%	50%	45%		47%	45%
≥$70,000	24%	29%	22%	0.13	21%	30%	0.23
Education
≤12 yrs	29%	21%	32%		28%	29%
Some college	32%	32%	32%		31%	35%
College graduate	17%	12%	20%		16%	20%
Masters degree/some graduate school	13%	22%	9%		15%	8%
Doctoral degree	9%	13%	7%	<0.001	9%	8%	0.29

For physical activity and annual income, sample size was lower because of missing data.

In population 2, fasting was associated (Figure 1) with lower risk of CAD (64% vs 76% CAD for fasting vs nonfasting, respectively; OR 0.55, 95% CI 0.35 to 0.87, p = 0.010), and this effect remained after multivariable adjustment for age, gender, BMI, hypertension, hyperlipidemia, diabetes, smoking, and family history (OR 0.46, 95% CI 0.27 to 0.81, p = 0.007). In the 74% of patients with data for physical activity, fasting results were similar in univariable analysis (OR 0.55, 95% CI 0.32 to 0.93, p = 0.025) and when adjusting for physical activity and the other cardiac risk factors listed (OR 0.50, 95% CI 0.26 to 0.95, p = 0.035). For the 68% with income and education data (n = 306), effect size was similar, but power was reduced (fasting OR 0.59, p = 0.06). However, adjustment for income and education did not alter the effect size of fasting (OR 0.57, p = 0.11). Adjusting for fasting and cardiac risk factors, physical activity (OR 0.78 per quintile, p = 0.043), and income (vs <$30,000/year, $30,000 to $69,999: OR 0.43, p = 0.046; ≥$70,000: OR 0.31, p = 0.016), but not education (OR 1.03 per category, p = 0.82), were associated with CAD.

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• Figure 1. 

  Univariable association of fasting with CAD, both overall and in subgroups. No effect modification was found for any covariable on the association of fasting with CAD (all p for interaction >0.15).

Most secondary behaviors differed by fasting status (Table 3), but only religious worship was associated with CAD, although some other trends were present (Table 4). Evaluation of alcohol use (any vs none) showed a trend toward increased CAD risk (Table 4), and evaluation by type and quantity showed a similar outcome for wine (any vs none: OR 1.70, 95% CI 0.91 to 3.19, p = 0.10), beer (1 to 7 drinks/week vs none: OR 1.20, 95% CI 0.60 to 2.40, p = 0.60; >7 drinks/week vs none: OR 1.56, 95% CI 0.43 to 5.64, p = 0.50), and liquor (1 to 7 drinks/week vs none: OR 1.81, 95% CI 0.85 to 3.87, p = 0.12; >7 drinks/week vs none: OR 4.08, 95% CI 0.52 to 32.26, p = 0.18). In analyses of fasting and the secondary behaviors, only fasting was significant in each model (Table 4) and in multivariable analysis (data not shown).

Table 3. Comparison of secondary behavioral measures to fasting status

Characteristic	Overall	Fasting	Nonfasting	p Value
LDS-proscribed beverages
Alcohol	28%	6%	35%	<0.001
Tea	31%	13%	38%	<0.001
Coffee	37%	10%	47%	<0.001
Religious observance
Religious worship	76%	97%	68%	<0.001
Day of rest	81%	93%	77%	<0.001
Receipt of social support
Talk about health	98%	97%	98%	0.55
Talk about personal problems	95%	94%	95%	0.58
Financial support	53%	56%	52%	0.54

Table 4. Association of fasting and secondary behavioral measures with coronary artery disease

Characteristic	Univariable OR (95% CI)	p Value	Modeled With Fasting OR (95% CI)	p Value
Fasting	0.55(0.35–0.87)	0.010	—	—
LDS-proscribed beverages
Alcohol	1.63(0.98–2.72)	0.06	1.40(0.82–2.39)	0.22
Tea	1.44(0.87–2.38)	0.15	1.23(0.73–2.08)	0.43
Coffee	1.42(0.88–2.28)	0.15	1.14(0.68–1.90)	0.62
Religious observance
Religious worship	0.54(0.31–0.93)	0.027	0.63(0.35–1.13)	0.12
Day of rest	0.92(0.51–1.65)	0.78	1.05(0.58–1.93)	0.87
Receipt of social support
Talk about health	0.90(0.18–4.53)	0.90	0.84(0.16–4.29)	0.83
Talk about personal problems	1.40(0.55–3.56)	0.48	1.36(0.53–3.50)	0.53
Financial support	0.87(0.55–1.39)	0.56	0.88(0.55–1.41)	0.60

Models entering fasting with each measure showed that none of the secondary measures was significant, whereas fasting retained significance at p <0.05 in all models.

In exploratory subgroup analyses (Figure 1), >30% lower risk of CAD was found in all subgroups, although not all achieved significance. Formal interaction tests found that no covariable modified the effect of fasting (all p for interaction >0.15). Notably, the effect of fasting on CAD was present in patients of religious preferences other than LDS (44% vs 78% CAD: OR 0.23, 95% CI 0.06 to 0.90, p = 0.037).

Finally, an exploratory evaluation was performed with inclusion of 67 patients with moderate CAD who had been excluded as indeterminate from all other analyses, bringing the population 2 sample size to 515. Diabetes prevalence was lower (11% vs 20% for fasting vs nonfasting, respectively; p = 0.019), and trends to lower BMI (27.9 ± 5.3 vs 29.1 ± 6.2 kg/m²; p = 0.051) and less hypertension (52% vs 61%; p = 0.07) were found. A stepwise trend in CAD (p for trend = 0.038) was found, with 34%, 26%, and 24% fasting reported in patients with no CAD, moderate CAD, and significant CAD, respectively.

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Discussion 

The Utah population consistently has 1 of the lowest rates of death from cardiovascular disease,¹ and this low-risk status has been linked to the lifestyle of people with an LDS religious preference.², ³ The most likely source of such risk differences is the proscription of tobacco smoking because smoking is a well-described risk factor for CAD development and conveys a substantial increase in risk,¹, ¹⁷ but it is improbable that smoking alone could account for such a profound effect.

This study confirmed an additional CAD risk difference based on routine fasting behavior and was the first to evaluate the association of routine fasting with angiographically defined CAD. Fasting was defined in the study as abstinence from food and drink for an extended period. This was designed to include the LDS definition and a broader set of other fasting definitions while retaining the periodic and routine aspects. Many religions encourage occasional fasting for purification and improving self-discipline,²¹, ²² and some contemporary wellness philosophies advocate prolonged fasting for bodily cleansing. LDS teachings provide for a once-monthly fast in which adherents do not eat or drink for 2 consecutive meals (i.e., 24 hours) and children are encouraged to fast as early as the age of 8 years, thus potentially establishing a pattern of fasting behavior early in life before the development of CAD.⁸

The lower risk of CAD may have occurred because fasting, or a behavior arising from it, is causally related to lower CAD risk. It may be that fasting improves an individual's self-control over bodily appetites and desires,⁸ which could translate into better discipline regarding daily caloric intake. Because this study did not evaluate caloric intake (i.e., diet), it was not clear whether diet or some dietary factor (e.g., vitamin, nutrient, or nutraceutical intake) may account for the finding. Because fasting-derived behavioral discipline (i.e., a “state of mind”) may account for the lower risk of CAD associated with fasting in this population, future investigation should evaluate dietary factors and self-discipline.

Conversely, the hypothesis that fasting may influence metabolic health is the more likely explanation based on evidence from the scientific literature. Decreased β-cell sensitivity to glucose (derangement of insulin secretion) and decreased sensitivity to insulin by peripheral tissues (insulin resistance) are well-established pathways in type 2 diabetes.¹³, ¹⁴ Desensitization of receptors to a stimulus is a well-known phenomenon that may occur quickly or after prolonged exposure to the stimulus.¹³ Because it periodically eliminates such exposure, routine fasting may represent a behavioral approach to temporarily eliminate receptor stimulation and reset cellular sensitivity to glucose and/or insulin by periodically resting the system.¹¹ If so, fasting would be associated not only with lower risk of CAD, but also with lower prevalence of diabetes, and this study found such associations. Because 18% of diabetic patients reported that they routinely fasted and had a lower risk of CAD compared with nonfasting diabetic patients, this suggested that fasting may reduce diabetes risk and should be further investigated.

Regarding glucose metabolism, Panowski et al²³ found that expression of the Caenorhabditis elegans defective pharynx development (PHA-4) gene was increased >80% because of fasting and, in separate experiments, that overexpression of PHA-4 increased longevity. The murine and human FOXA genes are orthologous to the C. elegans PHA-4 gene. FOXA is a family of transcription factors that, among other functions, regulate glucagon expression and glucose homeostasis and do so to a greater degree in response to fasting.²⁴ Other transporter and metabolic enzyme genes are also differentially expressed because of fasting,²⁵ and new evidence suggested that fasting (termed “short-term starvation”) may activate a self-protective cellular stress-resistance mechanism.²⁶ Such direct impacts of fasting on longevity and homeostasis provide biologically plausible mechanisms that may explain how routine fasting behavior across the life span could reduce such age-related chronic diseases as CAD.

It may be instructive to also consider other populations in which fasting behavior may be linked to diabetes or metabolic syndrome. It is increasingly evident that several ethnic populations whose ancestors historically experienced more frequent and severe feast-famine cycles than Caucasians are today enduring higher rates of diabetes and metabolic syndrome.²⁷ The higher rates of disease in those ethnic groups is the result of both modern environmental factors and a shared genetic ability to withstand extended periods without food,²⁷ which may also be described as the inherited ability to endure more frequent periods of fasting or caloric restriction.

Several reports indicated that limiting caloric intake (i.e., caloric restriction) may have antiaging¹³ and cardioprotective effects.⁹, ¹⁰, ¹¹ It is expected that caloric restriction will lead to improved cardiac risk profiles.⁹ Although fasting was associated with lower diabetes prevalence, only small and not statistically-significant differences in BMI and hypertension were found based on fasting behavior. Evidence suggested that multiple calorie-deprivation pathways may exist that improve health.²³ Thus, any direct connection between fasting and caloric restriction requires further exploration.

Finally, evidence in this report also suggested that fasting was associated with other behaviors common to this population. Patients who fasted were also more likely to not smoke, be more physically active, follow beverage proscriptions, engage in religious worship, and observe a day of rest. This allows for the possibility that fasting may simply be the best surrogate for a cluster of low-risk behaviors, including unmeasured factors. However, fasting behavior was reported by some with religious preferences other than LDS, and in these subjects, an association of large effect size was found (77% lower risk of CAD). This suggested that the observed benefit arose from fasting and not from a cluster of religion-associated behaviors. In addition, it was unlikely that the other behaviors (at least the measured ones) accounted for the fasting benefit because they were all eliminated when statistical modeling included them with fasting.

This study was potentially susceptible to various problems faced by all observational studies, including uncontrolled confounding, reverse causation, and self-selection in survey response. The association of religious preference with CAD was similar in both populations, and adjustment for various potential confounders did not eliminate or appreciably attenuate the association of fasting. Confirmatory studies in other populations are required because uncontrolled confounding may remain, including because of patient self-selection for survey response in this study's hospital care setting.

The LDS proscription of alcohol was notable because nonuse was associated in many studies with higher CAD risk compared with moderate levels of consumption.⁴ If so, CAD risk would be expected to increase in LDS adherents, but this study suggested that abstinence from alcohol was not associated with higher CAD risk. Although contrary to a commonly held belief, this finding was supported by reports that the benefits of moderate alcohol consumption may arise from residual confounding because of socioeconomic and other factors,²⁸, ²⁹, ³⁰ an issue that only a randomized clinical trial could resolve. The present study appears to be the first in which most subjects were nondrinkers. Thus, social and behavioral risk profiles of drinkers and nondrinkers in the present study may be at variance with previously studied populations.

This population was unique because of the mentioned behaviors and the primarily Caucasian ethnic composition. Thus, study findings may not be generalizable to other populations. Additional study of fasting in other geographic locations and in other ethnicities is indicated.

A strength of the study was the CAD outcome determined using coronary angiography, the gold-standard assessment of CAD status. Cases had clinically-significant coronary stenoses. Controls, although not a random population sample, were definitively free from coronary lesions.

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