The cross-sectional study design is sometimes avoided by researchers or considered an undesired methodology. Possible reasons include incomplete understanding of the research design, fear of bias, and uncertainty about the measure of association. Using causal diagrams and certain premises, we compared a hypothetical cross-sectional study of the effect of a fertility drug on pregnancy with a hypothetical cohort study. A side-by-side analysis showed that both designs call for a tradeoff between information bias and variance and that neither offers immunity to sampling colliding bias (selection bias). Confounding bias does not discriminate between the two designs either. Uncertainty about the order of causation (ambiguous temporality) depends on the nature of the postulated cause and the measurement method. We conclude that a cross-sectional study is not inherently inferior to a cohort study. Rather than devaluing the cross-sectional design, threats of bias should be evaluated in the context of a concrete study, the causal question at hand, and a theoretical causal structure.

Background

Population-based research on heart failure (HF) is hindered by lack of consensus on diagnostic criteria. Framingham (FRM), National Health and Nutrition Examination Survey (NHANES), Modified Boston (MBS), Gothenburg (GTH), and International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) code criteria do not differentiate acute decompensated heart failure (ADHF) from chronic stable HF. We developed a new classification protocol for identifying ADHF in the Atherosclerosis Risk in Communities (ARIC) Study and compared it with these other schemes.

Methods and Results

A sample of 1180 hospitalizations with a patient address in four study communities and eligible discharge codes were selected. After assessing whether the chart contained evidence of possible HF signs, 705 were fully abstracted. Two independent reviewers classified each case as ADHF, chronic stable HF or no HF using ARIC classification guidelines. Fifty-nine percent of cases met ARIC criteria for ADHF and 13.9% and 27.1% were classified as chronic stable HF or no HF, respectively. Among events classified as HF by FRM criteria, 68.4% were validated as ADHF, 9.6% as chronic stable HF and 21.9% as no HF. However, 92.5% of hospitalizations with a primary ICD-9-CM 428 “heart failure” code were validated as ADHF. Sensitivities of comparison criteria to classify ADHF ranged from 38 to 95%, positive predictive values from 62 to 92%, and specificities from 19 to 96%.

Conclusions

Although comparison criteria for classifying HF were moderately sensitive in identifying ADHF, specificity varied when applied to a randomly selected set of suspected HF hospitalizations in the community.

Analogous to rapid ventricular pacing, frequent ventricular premature complexes (VPCs) may predispose over time to cardiomyopathy and subsequent heart failure (HF). We examined the association of frequent VPCs with HF incidence in a population-based cohort, free of HF and coronary heart disease (CHD) at baseline. At study baseline (1987-89), at least one VPC on a 2-minute rhythm ECG strip was seen in 5.5% (739/13486) of the middle aged (45-64 years old at baseline), white and African-American, men and women of the ARIC cohort. Incident HF was defined as the first appearance of ICD code ‘428.x’ in hospital discharge record or death certificate through 2005. Over an average follow up of 15.6 years, incident HF was seen in 10% subjects (19.4% in those with VPCs vs. 9.4% in those without). The age, race, and gender adjusted hazard ratio (HR) of HF for VPCs was 1.89 (95% CI = 1.59, 2.24). After multivariable adjustment for potential confounders, HR (95% CI) of HF for those with any VPC vs. no VPCs was 1.63 (1.36, 1.96). After additional adjustment for incident CHD as a time-varying covariate, the HR (95% CI) was 1.71 (1.42, 2.08). Presence of higher frequency of VPCs or complex VPCs had similar rates of HF as compared to single VPC and all were higher than no VPC group. In conclusion, in this large population based cohort, presence of VPCs is associated with incident HF independent of incident CHD.

Background and Purpose

Carotid intima-media thickness (IMT) and electrocardiographic left ventricular hypertrophy (ECG-LVH) are two subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased IMT and ECG-LVH also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid IMT and the presence of ECG-LVH would be independently associated with increased ICH incidence.

Methods

Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid IMT, carotid plaque, and ECG-LVH. Over a median of 18 years of follow-up, 162 incident ICH events occurred.

Results

After adjustment for other ICH risk factors, carotid IMT was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific quartile 1, elevated 1.6 to 2.6-fold in quartiles 2–3, and elevated 2.5 to 3.7-fold in quartile 4 (p<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI = 1.1–3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI = 0.76–2.0) greater ICH risk in ARIC. ECG-LVH carried a hazard ratio of ICH of 1.7 (95% CI = 0.77–3.7) in CHS and 2.8 (95% CI = 1.2–6.4) in ARIC.

Conclusions

Our data suggest that people with carotid atherosclerosis and possibly LVH are at increased risk not only of ischemic stroke but also of ICH.

It is tempting to assume that confounding bias is eliminated by choosing controls that are identical to the cases on the matched confounder(s). We used causal diagrams to explain why such matching not only fails to remove confounding bias, but also adds colliding bias, and why both types of bias are removed by conditioning on the matched confounder(s). As in some publications, we trace the logic of matching to a possible tradeoff between effort and variance, not between effort and bias. Lastly, we explain why the analysis of a matched case-control study – regardless of the method of matching – is not conceptually different from that of an unmatched study.

Background and Purpose

Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke.

Methods

Between 1987 and 1989, 13,560 men and women aged 45 to 64 years and free of clinical stroke, took part in the first examination of the Atherosclerosis Risk in Communities study. Incident strokes were ascertained by hospital surveillance.

Results

During an average follow up of 15.7-years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness (IMT) levels. Although this positive association was observed for all stroke subtypes, the age-, sex-, and race-adjusted risk ratios (RR) were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61mm), the adjusted RRs for those in the highest quintile (≥0.85mm) of IMT were 2.55 (95%CI, 1.09 to 5.94) for hemorrhagic, 2.89 (95%CI, 1.50 to 5.54) for lacunar, 3.61 (95%CI, 2.33 to 5.99) for nonlacunar, and 6.12 (95%CI, 2.71 to 13.9) for cardioembolic stroke. The RRs were attenuated by additional adjustment for covariates, but remained statistically significant for nonlacunar and cardioembolic strokes (p for trend <0.001, respectively). The association between carotid IMT and lacunar stroke was somewhat stronger in African Americans than in whites (P for interaction = 0.07).

Conclusions

Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.

To compare the sleep-disordered breathing prevalence among Hispanic and white Americans and Japanese, we performed a one-night sleep study with a single channel airflow monitor on 211 Hispanics and 246 whites from the Minnesota Field Center of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan.

The respiratory disturbance index and sleep-disordered breathing, defined as respiratory disturbance index ≥ 15 disturbances/hr, were estimated. The sleep-disordered breathing prevalence was higher in men (34.2%) than women (14.8%), and higher among Hispanics (36.5%) and whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when we adjusted for body mass index instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans.

The sleep-disordered breathing prevalence was lower among Japanese than the Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.

Background

Clinic-based observational studies in men have reported that obstructive sleep apnea (OSA) is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of OSA to incident coronary heart disease and heart failure in a general community sample of adult men and women.

Methods and Results

A prospective, longitudinal epidemiologic study of 1927 men and 2495 women aged ≥ 40 years and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed for a median of 8.7 years. After adjustment for multiple risk factors, OSA was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men age ≤70 years (adjusted hazard ratio 1.10 [95% CI 1.00, 1.21] per 10-unit increase in apnea-hypopnea index [AHI]), but not in older men or in women of any age. Among men age 40–70 years, those with AHI ≥30 were 68% more likely to develop coronary heart disease than those with AHI <5. OSA predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% CI 1.02, 1.26] per 10-unit increase in AHI). Men with AHI ≥30 were 58% more likely to develop heart failure than those with AHI <5.

Conclusion

OSA is associated with increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.

Rationale: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population.

Objectives: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea.

Methods: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea–hypopnea index (OAHI) and outcome was incident ischemic stroke.

Measurements and Main Results: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1–7.4). In the mild to moderate range (OAHI, 5–25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2–10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25.

Conclusions: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.

Background. Recent studies report that acute stroke patients who present to the hospital on weekends have higher rates of 28-day mortality than similar patients who arrive during the week. However, how this association is related to clinical presentation and stroke type has not been systematically investigated. Methods and Results. We examined the association between day of arrival and 28-day mortality in 929 validated stroke events in the ARIC cohort from 1987–2004. Weekend arrival was defined as any arrival time from midnight Friday until midnight Sunday. Mortality was defined as all-cause fatal events from the day of arrival through the 28th day of followup. The presence or absence of thirteen stroke signs and symptoms were obtained through medical record review for each event. Binomial logistic regression was used to estimate odds ratios and 95% confidence intervals (OR; 95% CI) for the association between weekend arrival and 28-day mortality for all stroke events and for stroke subtypes. The overall risk of 28-day mortality was 9.6% for weekday strokes and 10.1% for weekend strokes. In models controlling for patient demographics, clinical risk factors, and event year, weekend arrival was not associated with 28-day mortality (0.87; 0.51, 1.50). When stratified by stroke type, weekend arrival was not associated with increased odds of mortality for ischemic (1.17, 0.62, 2.23) or hemorrhagic (0.37; 0.11, 1.26) stroke patients. Conclusions. Presence or absence of thirteen signs and symptoms was similar for weekday patients and weekend patients when stratified by stroke type. Weekend arrival was not associated with 28-day all-cause mortality or differences in symptom presentation for strokes in this cohort.

Background

Ventricular premature complexes (PVCs) on a 2-minute electrocardiogram (ECG) are a common, largely asymptomatic finding, associated with increased risk of coronary heart disease (CHD) and death. They may reflect atherosclerosis or other pathogenic pathways that predispose to arrhythmias and stroke.

Methods/Results

We conducted a prospective evaluation of the Atherosclerosis Risk In Communities Study cohort (n=14,783) of middle aged men and women to assess whether the presence of PVCs at study baseline (1987-89) influenced the risk of incident stroke through 31st December 2004. PVCs were seen in 6.1% of the participants at baseline, and 729 (4.9%) had incident stroke. The unadjusted cumulative proportion of incident stroke in individuals with any PVC was 6.6% compared to 4.1% in those without PVC. The unadjusted hazard ratio (HR) of incident stroke in individuals with any PVC compared to those without any PVCs was 1.71 (95% Confidence Interval (CI) 1.33, 2.20).

Among individuals without hypertension and diabetes at baseline, PVCs were independently associated with incident stroke (HR: 1.72 (1.14, 2.59)). Among those with either diabetes or hypertension the presence of any PVCs did not increase the risk of stroke. The association was stronger for non-carotid embolic stroke than for thrombotic stroke and its magnitude increased with higher frequency of PVCs.

Conclusions

Frequent PVCs are associated with risk of incident stroke in participants free of hypertension and diabetes. This suggests that PVCs may contribute to atrio-ventricular remodeling or may be risk marker for incident stroke, particularly embolic stroke.

Objectives

This study sought to evaluate respiratory disturbances as potential triggers for arrhythmia in those with sleep-disordered breathing (SDB).

Background

SDB is associated with increased risk of atrial fibrillation (AF) and non-sustained ventricular tachycardia (NSVT) as well as a predilection for sudden cardiac death during nocturnal sleeping hours. However, prior research has not established whether respiratory disturbances operate as triggers for nocturnal arrhythmias.

Methods

Overnight polysomnograms (PSGs) from the Sleep Heart Health Study (n = 2816) were screened for paroxysmal atrial fibrillation (PAF) and NSVT. We used the case-crossover design to determine whether apneas and/or hypopneas are temporally associated with episodes of PAF or NSVT. For each arrhythmia, 3 periods of sinus rhythm were identified as control intervals. PSGs were examined for the presence of respiratory disturbances, oxygen desaturations, and cortical arousals within a 90-second hazard period preceding each arrhythmia or control period.

Results

Fifty-seven participants with a wide range of SDB contributed 62 arrhythmias (76% NSVT). The odds of an arrhythmia following a respiratory disturbance were nearly 18-times (OR 17.5; 95% CI 5.3–58.4) the odds of an arrhythmia occurring following normal breathing. The absolute rate of arrhythmia associated with respiratory disturbances was low (1 excess arrhythmia/40000 respiratory disturbances). Neither hypoxia nor EEG-defined arousals alone increased arrhythmia risk.

Conclusions

Although the absolute arrhythmia rate is low, the relative risk of PAF and NSVT during sleep is markedly increased shortly after a respiratory disturbance. These results support a direct temporal link between SDB events and the development of these arrhythmias.

BACKGROUND

Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease.

METHODS

We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below −910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects.

RESULTS

Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (−4.1 ml; 95% confidence interval [CI], −3.3 to −4.9; P<0.001), stroke volume (−2.7 ml; 95% CI, −2.2 to −3.3; P<0.001), and cardiac output (−0.19 liters per minute; 95% CI, −0.14 to −0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction.

CONCLUSIONS

In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.

Rationale: Cross-sectional epidemiologic studies show an association between sleep-disordered breathing and hypertension, but only one cohort study has examined sleep-disordered breathing as a risk factor for incident hypertension.

Objectives: To examine whether sleep-disordered breathing increases the risk of incident hypertension among persons 40 years of age and older.

Methods: In a prospective cohort study, we analyzed data from 2,470 participants who at baseline did not have hypertension, defined as blood pressure of at least 140/90 mm Hg or taking antihypertensive medication. The apnea-hypopnea index (AHI), the number of apneas plus hypopneas per hour of sleep, was measured by overnight in-home polysomnography. We estimated odds ratios for developing hypertension during 5 years of follow-up according to baseline AHI.

Measurements and Main Results: The odds ratios for incident hypertension increased with increasing baseline AHI; however, this relationship was attenuated and not statistically significant after adjustment for baseline body-mass index. Although not statistically significant, the observed association between a baseline AHI greater than 30 and future hypertension (odds ratio, 1.51; 95% confidence interval, 0.93–2.47) does not exclude the possibility of a modest association.

Conclusions: Among middle-aged and older persons without hypertension, much of the relationship between AHI and risk of incident hypertension was accounted for by obesity. After adjustment for body mass index, the AHI was not a significant predictor of future hypertension, although a modest influence of an AHI greater than 30 on hypertension could not be excluded.

BACKGROUND

The genes underlying the risk of stroke in the general population remain undetermined.

METHODS

We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [±SD] age, 63±8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS

Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5×10−8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS

A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

OBJECTIVE

To determine whether middle-aged and older individuals with impaired fasting glucose (IFG), but no clinical evidence of cardiovascular disease, exhibit abnormal changes in proximal thoracic aortic stiffness or left ventricular (LV) mass when compared with healthy counterparts.

RESEARCH DESIGN AND METHODS

From the Multi-Ethnic Study of Atherosclerosis, 2,240 subjects with normal fasting glucose (NFG), 845 with IFG, and 414 with diabetes, all aged 45 to 85 years and without preexisting coronary artery disease, underwent MRI determinations of total arterial and proximal thoracic aortic stiffness and LV mass. The presence or absence of other factors known to influence arterial stiffness was assessed.

RESULTS

After adjustment for clinical factors known to modify arterial stiffness, proximal thoracic aortic stiffness was not increased in those with IFG compared with those with NFG (1.90 ± 0.05 versus 1.91 ± 0.04 10−3 mmHg−1, respectively, P = 0.83). After accounting for clinical factors known to influence LV mass, LV mass was increased in those with diabetes relative to those with NFG (150.6 ± 1.4 versus 145.8 ± 0.81 g, P < 0.0009) but not in those with IFG in comparison with NFG (145.2 ± 1.03 versus 145.8 ± 0.81 g, P = 0.56).

CONCLUSIONS

Middle-aged and older individuals with the pre-diabetes state of IFG do not exhibit abnormal proximal thoracic distensibility or LV hypertrophy relative to individuals with NFG. For this reason, an opportunity may exist in those with IFG to prevent LV hypertrophy and abnormal aortic stiffness that is observed in middle-aged and older individuals with diabetes.

PURPOSE

An association of low plasma HDL-cholesterol with risk of breast cancer has been suggested by multiple studies; the evidence, however, is not conclusive. We examined the possible association of low HDL-cholesterol with incidence of breast cancer using data from the Atherosclerosis Risk in Communities Study (ARIC) cohort, a prospective study of a randomly selected sample of women and men from four US communities.

METHODS

Among 7,575 female members of the ARIC cohort, 359 cases of incident breast cancer were ascertained during the follow-up from 1987 through 2000. In analysis adjusted for age, race, body mass index, smoking, and reproductive variables we observed no association of low baseline HDL-cholesterol (<50 mg/dL) with incident breast cancer in the total sample (HR=1.08(95% CI 0.84, 1.40)) and a modest association (HR=1.67 (95% CI 1.06, 2.63) among women who were pre-menopausal at baseline. No association was observed among women who were post-menopausal at baseline. Removal from analysis of the first five years of follow-up did not appreciably change the observed associations.

CONCLUSION

Results of our study suggest that low HDL-cholesterol among pre-menopausal women may be a marker of increased breast cancer risk.

In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.

Background

Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

Methods and Findings

We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

Conclusions

Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.

Why Was This Study Done?

Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.

What Did the Researchers Do and Find?

At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.

What Do These Findings Mean?

These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000132.

The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)

The UK National Heath Service also provides information for patients about sleep apnea

MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)

More information on the Sleep Heart Health Study is available

Objective

To evaluate whether post menopausal hormones are associated with atherosclerosis.

Methods

We studied the relation of hormone use to coronary calcification and carotid intima-media thickness in a cross-sectional sample of 3,245 post menopausal women, of whom 1,620 had used hormones for various periods. Adjusted associations with three measures of hormone use (ever use, duration, and type of hormone) were estimated by multivariable regression.

Results

The prevalence of coronary calcification was only 4 percentage points lower in women who had ever used hormones than in women who had not (40% versus 44%), and was not monotonically related to longer use: ≤ 2 years: 38%; 2–6 years: 36%; 6–13 years: 41%; >13 years: 48%. Similarly, duration of hormone use did not show a monotonic dose-response relation with the calcium score. Mean differences in carotid intima-media thickness according to categories of years of hormone use and type of hormone ranged from −0.10 mm to +0.08 mm, with no consistent patterns. Most adjusted associations were weak and sometimes contrary to our expectation.

Conclusions

We did not find meaningful associations between hormone use and subclinical atherosclerosis—neither to support benefit or harm, nor to support the prevailing theory of “healthy user” bias (namely, inverse associations due to residual confounding).

Purpose

To describe the relationship of retinal arteriolar and venular caliber with cardiovascular risk factors, including inflammatory biomarkers, in a multiethnic population of whites, blacks, Hispanics, and Chinese.

Methods

A cross-sectional study comprising 5979 persons aged 45 to 84 years residing in six U.S. communities. Retinal vascular caliber was measured and summarized from digital retinal photographs. Standard cardiovascular risk factors, including biomarkers of inflammation (e.g., high-sensitivity C-reactive protein [hsCRP], interleukin [IL]-6, and plasma fibrinogen) and endothelial dysfunction (e.g., soluble intercellular adhesion molecule [sICAM]-1 [, plasminogen activator inhibitor [PAI]-1) were assessed.

Results

Mean retinal arteriolar caliber was 144.1 ± 14.4 (SD) μm, and venular caliber 214.0 ± 22.2 μm. In models controlling for age, gender, race-ethnicity, and center, smaller retinal arteriolar caliber was related to higher systolic and diastolic blood pressure, hypertension status, current alcohol consumption, greater body mass index, and higher levels of total homocysteine; larger retinal arteriolar caliber was related to diabetes, current cigarette smoking, and higher levels of plasma fibrin-ogen; and larger retinal venular caliber was related to diabetes, current cigarette smoking, greater body mass index and waist-hip ratio, higher levels of serum glucose, plasma triglyceride, plasma LDL-cholesterol, hsCRP, plasma fibrinogen, IL6, sICAM-1, and PAI-1 and lower levels of HDL-cholesterol. In multivariate analyses, blacks and Hispanics had larger retinal arteriolar and venular calibers than did whites and Chinese.

Conclusions

Retinal arteriolar and venular caliber is associated with a range of cardiovascular risk factors, including hypertension, diabetes, measures of obesity, and dyslipidemia. Venular caliber is also associated with systemic inflammation.

OBJECTIVES

This study assessed the cross-sectional association between coronary artery calcification (CAC) and myocardial perfusion in an asymptomatic population.

BACKGROUND

Clinical studies showed that the prevalence of stress-induced ischemia increased with CAC burden among patients with coronary heart disease (CHD). Whether an association between CAC and myocardial perfusion exists in subjects without a history of CHD remains largely unknown.

METHODS

A total of 222 men and women, ages 45 to 84 years old and free of CHD diagnosis, in the Minnesota field center of the MESA (Multi-Ethnic Study of Atherosclerosis) were studied. Myocardial blood flow (MBF) was measured using magnetic resonance imaging during rest and adenosine-induced hyperemia. Perfusion reserve was calculated as the ratio of hyperemic to resting MBF. Agatston CAC score was determined from chest multidetector computed tomography.

RESULTS

Mean values of hyperemic MBF and perfusion reserve, but not resting MBF, were monotonically lower across increasing CAC levels. After adjusting for age and gender, odds ratios (95% confidence intervals) of reduced perfusion reserve (<2.5) for subjects with CAC scores of 0, 0.1 to 99.9, 100 to 399, and ≥400 were 1.00 (reference), 2.16 (0.96 to 4.84), 2.81 (1.04 to 7.58), and 4.99 (1.73 to 14.4), respectively. Further adjustment for other coronary risk factors did not substantially modify the association. However, the inverse association between perfusion reserve and CAC attenuated with advancing age (p for interaction < 0.05).

CONCLUSIONS

Coronary vasodilatory response was associated inversely with the presence and severity of CAC in asymptomatic adults. Myocardial perfusion could be impaired by or manifest the progression to subclinical coronary atherosclerosis in the absence of clinical CHD.

Rationale: Sleep-disordered breathing recurrent intermittent hypoxia and sympathetic nervous system activity surges provide the milieu for cardiac arrhythmia development.

Objective: We postulate that the prevalence of nocturnal cardiac arrhythmias is higher among subjects with than without sleep-disordered breathing.

Methods: The prevalence of arrhythmias was compared in two samples of participants from the Sleep Heart Health Study frequency-matched on age, sex, race/ethnicity, and body mass index: (1) 228 subjects with sleep-disordered breathing (respiratory disturbance index ⩾ 30) and (2) 338 subjects without sleep-disordered breathing (respiratory disturbance index < 5).

Results: Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy (nonsustained ventricular tachycardia or bigeminy or trigeminy or quadrigeminy) were more common in subjects with sleep-disordered breathing compared with those without sleep-disordered breathing: 4.8 versus 0.9% (p = 0.003) for atrial fibrillation; 5.3 versus 1.2% (p = 0.004) for nonsustained ventricular tachycardia; 25.0 versus 14.5% (p = 0.002) for complex ventricular ectopy. Compared with those without sleep-disordered breathing and adjusting for age, sex, body mass index, and prevalent coronary heart disease, individuals with sleep-disordered breathing had four times the odds of atrial fibrillation (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.03–15.74), three times the odds of nonsustained ventricular tachycardia (OR, 3.40; 95% CI, 1.03–11.20), and almost twice the odds of complex ventricular ectopy (OR, 1.74; 95% CI, 1.11–2.74). A significant relation was also observed between sleep-disordered breathing and ventricular ectopic beats/h (p < 0.0003) considered as a continuous outcome.

Conclusions: Individuals with severe sleep-disordered breathing have two- to fourfold higher odds of complex arrhythmias than those without sleep-disordered breathing even after adjustment for potential confounders.

Background

Population-based secular trends in survival of patients with congestive heart failure (CHF) are central to public health research on the burden of the syndrome.

Methods

Patients 35–79 years old with a CHF discharge code in 1995 or 2000 were identified in 22 Minneapolis-St. Paul hospitals. A sample of the records was abstracted (50% of 1995 records; 38% of 2000 records). A total of 2,257 patients in 1995 and 1,825 patients in 2000 were determined to have had a CHF-related hospitalization. Each patient was followed for one year to ascertain vital status.

Results

The risk profile of the 2000 patient cohort was somewhat worse than that of the 1995 cohort in both sex groups, but the distributions of age and left ventricular ejection fraction were similar. Within one year of admission in 2000, 28% of male patients and 27% of female patients have died, compared to 36% and 27% of their counterparts in 1995, respectively. In various Cox regression models the average year effect (2000 vs. 1995) was around 0.75 for men and 0.95 to 1.00 for women. The use of angiotensin converting-enzyme inhibitors and beta-blockers was associated with substantially lower hazard of death during the subsequent year.

Conclusion

Survival of men who were hospitalized for CHF has improved during the second half of the 1990s. The trend in women was very weak, compatible with little to no change. Documented benefits of angiotensin converting-enzyme inhibitors and beta-blockers were evident in these observational data in both men and women.