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1.  Associations of Aortic Distensibility and Arterial Elasticity With Long-Term Visit-to-Visit Blood Pressure Variability: The Multi-Ethnic Study of Atherosclerosis (MESA) 
American Journal of Hypertension  2013;26(7):896-902.
Although higher visit-to-visit variability (VVV) of blood pressure (BP) is associated with increased cardiovascular disease risk, the physiological basis for VVV of BP is incompletely understood.
We examined the associations of aortic distensibility (assessed by magnetic resonance imaging) and artery elasticity indices (determined by radial artery pulse contour analysis) with VVV of BP in 2,640 and 4,560 participants, respectively, from the Multi-Ethnic Study of Atherosclerosis. Arterial measures were obtained at exam 1. BP readings were taken at exam 1 and at 3 follow-up visits at 18-month intervals (exams 2, 3, and 4). VVV was defined as the SD about each participant’s mean systolic BP (SBP) across visits.
The mean SDs of SBP were inversely associated with aortic distensibility: 7.7, 9.9, 10.9, and 13.2mm Hg for quartiles 4, 3, 2, and 1 of aortic distensibility, respectively (P trend < 0.001). This association remained significant after adjustment for demographics, cardiovascular risk factors, mean SBP, and antihypertensive medication use (P trend < 0.01). In a fully adjusted model, lower quartiles of large artery and small artery elasticity (LAE and SAE) indices were also associated with higher mean SD of SBP (P trend = 0.02 for LAE; P trend < 0.001 for SAE).
In this multiethnic cohort, functional alterations of central and peripheral arteries were associated with greater long-term VVV of SBP.
PMCID: PMC3693480  PMID: 23537891
arteries; blood pressure; epidemiology; hypertension; vasculature.
2.  Alterations in Diastolic Function in Masked Hypertension: Findings from the Masked Hypertension Study 
American Journal of Hypertension  2013;26(6):808-815.
In a prior study of patients with diabetes, diastolic function was similarly impaired in masked hypertension (MHT) and sustained hypertension (SHT). We evaluated whether MHT is associated with impaired diastolic function compared with SHT and sustained normotension (NT) in the general population.
From February 2005 to December 2010, 798 participants without a history of cardiovascular disease or treated hypertension, were enrolled in the Masked Hypertension Study. Participants underwent clinic blood pressure (CBP) and 24-hour ambulatory blood pressure (ABP) measurements. A 2-dimensional Doppler echocardiogram was performed to evaluate diastolic function,s cardiac structure, volume, and systolic function. The 9 CBPs obtained across 3 clinic visits and awake ABP measurements were averaged. Clinic hypertension was defined as systolic/diastolic blood pressure (SBP/DBP) ≥ 140/90 mmHg. Ambulatory hypertension was defined as awake SBP/DBP ≥ 135/85mm Hg. MHT was defined as having ambulatory but not clinic hypertension. White-coat hypertensives (n = 8) were excluded from the analysis.
Of the 790 participants, 116 (14.7%) participants had MHT, 37 (4.7%) participants had SHT, and 637 (80.6%) participants had NT. After age, sex, race/ethnicity, and body mass index adjustment, compared with NT, E’-velocities were significantly lower in MHT (P < 0.01) and SHT (P < 0.05), and E/E’ ratios were significantly higher MHT (P < 0.05) and SHT (P < 0.05). These associations were independent of left ventricular mass. Diastolic function parameters did not significantly differ between MHT and SHT.
Diastolic function was impaired in MHT compared with NT independent of changes in left ventricular mass.
PMCID: PMC3657486  PMID: 23446956
ambulatory blood pressure monitoring; blood pressure;  echocardiography; hypertension.
3.  A Pilot Study Identifying Statin Non-adherence With Visit-to-visit Variability of Low Density Lipoprotein-Cholesterol 
The American journal of cardiology  2013;111(10):1437-1442.
Non-adherence to cardiovascular medications such as statins is a common, important problem. Clinicians currently rely on intuition to identify medication non-adherence. The visit-to-visit variability (VVV) of LDL-C may represent an opportunity to identify statin non-adherence with greater accuracy. We examined the clinical and pharmacy data from 782 members of the Boston Medical Center (BMC) Health Plan, seen at either BMC or its affiliated Community Health Centers, who were taking statins and had at least 3 LDL-C measurements between 2008 and 2011. The LDL-C VVV (defined by the within-patient standard deviation) was categorized into quintiles. Multivariable logistic regression models were generated with statin non-adherence (defined by the standard 80% pharmacy refill based medication possession ratio threshold) as the dependent variable. The proportion of statin non-adherence increased across quintiles of LDL-C VVV (64.3%, 71.2%, 89.2%, 92.3%, 91.7%). Higher quintiles of LDL-C VVV had a strong positive association with statin non-adherence with an adjusted odds ratio of 3.4 (CI: 1.7–7.1) in the highest versus lowest quintile of LDL-C VVV. The age and gender adjusted model had poor discrimination [C-statistic 0.62 (CI: 0.57, 0.67)] while the final adjusted (age, gender, race, mean LDL-C) model demonstrated good discrimination [C-statistic 0.75 (CI: 0.71, 0.79)] between adherent and non-adherent patients. In conclusion, the VVV of LDL-C demonstrated a strong association with statin non-adherence in a clinic setting. Further, a VVV- of LDL-C based model has good discrimination characteristics for statin non-adherence. Research is needed to validate and generalize these findings to other populations and biomarkers.
PMCID: PMC3644321  PMID: 23433758
Visit-to-visit variability; statins; medication adherence
4.  Pulmonary Hyperinflation and Left Ventricular Mass 
Circulation  2013;127(14):1503-1511e6.
Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass.
Methods and results
The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50–79 years who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure and other cardiac risk factors.
Among 119 MESA COPD Study participants, mean age was 69±6 years, 55% were male and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 grams. Residual lung volume was independently associated with greater LV mass (7.2 grams per standard deviation increase in residual volume; 95% CI 2.2 to 12; P=0.004), and was similar in magnitude to that of systolic blood pressure (7.6 grams per standard deviation increase in systolic blood pressure, 95% CI 4.3 to 11 grams; p<0.001). Similar results were observed for LV mass to end-diastolic volume ratio (p=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009).
Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.
PMCID: PMC4018203  PMID: 23493320
Left ventricular mass; hyperinflation; chronic obstructive pulmonary disease
5.  The ‘Perfect Storm’ and Acute Coronary Syndrome Onset: Do Psychosocial Factors Play a Role? 
The revolution in cardiac care over the past two decades, characterized by emergent revascularization, drug eluting stents, anti-platelet medications, and advanced imaging has had little impact on overall ACS recurrence, or ACS prevention. The “Perfect Storm” refers to a confluence of events and processes, including atherosclerotic plaque, coronary flow dynamics, hemostatic and fibrinolytic function, metabolic and inflammatory conditions, neurohormonal dysregulation, and environmental events that give rise to, and result in an ACS event. In this article we illustrate the limits of the traditional main effect research model, giving a brief description of the current state of knowledge regarding the development of atherosclerotic plaque and the rupturing of these plaques that defines an ACS event. We then apply the Perfect Storm conceptualization to describe a program of research concerning a psychosocial vulnerability factor that contributes to increased risk of recurrent ACS and early mortality, and that has defied our efforts to identify underlying pathophysiology and successfully mount efforts to fully mitigate this risk.
PMCID: PMC3652628  PMID: 23621970
7.  Relation between Leukocyte Telomere Length and Incident Coronary Heart Disease Events (From the 1995 Canadian Nova Scotia Health Survey) 
The American journal of cardiology  2013;111(7):962-967.
Leukocyte telomere length has been proposed as a biomarker of cellular aging and atherosclerosis. We sought to determine whether leukocyte telomere length is independently associated with incident coronary heart disease (CHD) in the general population. Telomere length was measured using a polymerase chain reaction method for participants enrolled in the 1995 Nova Scotia Health Survey (n=1,917). The primary endpoint was first occurrence of fatal and non-fatal CHD events. During a mean follow-up of 8.7 years, 164 fatal or non-fatal CHD events occurred. Compared to participants in the longest tertile of telomere length, those in the middle and shortest tertiles had increased incidence of CHD events (6.2, 11.2 and 12.2 per 1000 person-years, respectively). After adjustment for demographics, traditional risk factors and inflammatory markers including hs-CRP, IL-6, and sICAM-1, those in the middle tertile had significantly elevated risk for incident CHD (hazard ratio [HR] 1.63, 95% CI 1.07–2.51, p=0.02) compared to the longest tertile, whereas the risk for those in the shortest tertile was non-significantly elevated (HR 1.25, 95% CI 0.82–1.90, p=0.30). In conclusion, these findings do not support a linear association between leukocyte telomere length and incident CHD risk in the general population.
PMCID: PMC3602395  PMID: 23375186
coronary heart disease; telomere; risk prediction
Journal of human hypertension  2013;27(10):617-622.
Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1,897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor – α [TNFα], resistin and total adiponectin. The mean age and body mass index was 64.7 years and 28.1 respectively, and 50% were female. After adjustment for risk factors, a 1-standard deviation increment higher leptin level was significantly associated with higher systolic (5.0 mmHg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (p < 0.01 for all). These associations were not materially different when the other adipokines, as well as body mass index, waist circumference or waist to hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, body mass index or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines.
PMCID: PMC3735864  PMID: 23535989
adipokine; leptin; blood pressure; hypertension; ethnicity
9.  C-reactive protein level and the incidence of eligibility for statin therapy: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Clinical cardiology  2012;36(1):15-20.
Given the results of the JUPITER trial, statin initiation may be considered for individuals with elevated high sensitivity C-reactive protein (CRP). However, if followed prospectively, many individuals with elevated CRP may become statin-eligible, limiting the impact of elevated CRP as a treatment indication. This analysis estimates the proportion of people with elevated CRP that become statin eligible over time.
We followed 2,153 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of cardiovascular disease (CVD) and diabetes with LDL-cholesterol (LDL-C) <130 mg/dL at baseline to determine the proportion who become eligible for statins over 4.5 years. The proportion eligible for statin therapy, defined by the National Cholesterol Education Program (NCEP) 2004 updated guidelines, was calculated at baseline and during follow-up stratified by baseline CRP level (≥2 mg/L).
At baseline, 47% of the 2,153 participants had elevated CRP. Among participants with elevated CRP, 29% met NCEP criteria for statins, compared to 28% without elevated CRP at baseline. By 1.5 years later, 26% and 22% (p=0.09) of those with and without elevated CRP at baseline reached NCEP LDL-C criteria and/or had started statins, respectively. These increased to 42% and 39% (p=0.24) at 3 years and 59% and 52% (p=0.01) at 4.5 years following baseline.
A substantial proportion of those with elevated CRP did not achieve NCEP based statin eligibility over 4.5 years of follow-up. These findings suggest that many patients with elevated CRP may not receive the benefits of statins if CRP is not incorporated into the NCEP screening strategy.
PMCID: PMC3953418  PMID: 22886783
10.  Accumulation of Non-Traditional Risk Factors for Coronary Heart Disease Is Associated with Incident Coronary Heart Disease Hospitalization and Death 
PLoS ONE  2014;9(3):e90475.
Assessing multiple traditional risk factors improves prediction for late-life diseases, including coronary heart disease (CHD). It appears that non-traditional risk factors can also predict risk. The objective was to investigate contributions of non-traditional risk factors to coronary heart disease risk using a deficit accumulation approach.
Community-dwelling adults with no known history of CHD (n = 2195, mean age 46.9±18.7 years, 51.8% women) participated in the 1995 Nova Scotia Health Survey. Three risk factor indices were constructed to quantify the proportion of deficits present in individuals: 1) a 17-item Non-Traditional Risk Factor Index (e.g. sinusitis, arthritis); 2) a 9-item Traditional Risk Factor Index (e.g. hypertension, diabetes); and 3) a frailty index (25 items combined from the other two index measures). Ten-year risks of CHD events (defined as CHD-related hospitalization and CHD-related mortality) were evaluated.
The Non-Traditional Risk Factor Index, made up of health deficits unrelated to CHD, was independently associated with incident CHD events over 10 years after controlling for age, sex, and the Traditional Risk Factor Index [adjusted {adj.} Hazard Ratio {HR} = 1.31; Confidence Interval {CI} 1.14–1.51]. When all health deficits, both those related and unrelated to CHD, were included in a frailty index the corresponding adjusted hazard ratio was 1.61; CI 1.40–1.85.
Both traditional and non-traditional risk factor indices are independently associated with incident CHD events. CHD risk assessment may benefit from consideration of general health information as well as from traditional risk factors.
PMCID: PMC3953643  PMID: 24625791
11.  Behavioral Mechanisms, Elevated Depressive Symptoms, and the Risk for Myocardial Infarction or Death in Individuals with Coronary Heart Disease (A Reason for Geographic and Racial Differences in Stroke [REGARDS] Study) 
To determine whether behavioral mechanisms explain the association between depressive symptoms and myocardial infarction (MI) or death in individuals with coronary heart disease (CHD).
Depressive symptoms are associated with increased morbidity and mortality in individuals with CHD, but it is unclear how much behavioral mechanisms contribute to this association.
The study included 4,676 participants with a history of CHD. Elevated depressive symptoms were defined as scores ≥4 on the Center for Epidemiologic Studies Depression 4-item Scale. The primary outcome was definite/probable MI or death from any cause. Incremental proportional hazards models were constructed by adding demographics, comorbidities and medications, then four behavioral mechanisms (alcohol use, smoking, physical inactivity, and medication non-adherence).
At baseline, 638 (13.6%) participants had elevated depressive symptoms. Over a median 3.8 years of follow up, 125 of 638 (19.6%) participants with and 657 of 4038 (16.3%) without elevated depressive symptoms had events. Higher risk of MI or death was observed for elevated depressive symptoms after adjusting for demographics (hazard ratio [HR] 1.41, 95% CI 1.15–1.72), but was no longer significant after adjusting for behavioral mechanisms (HR 1.14, 95% CI 0.93–1.40). The four behavioral mechanisms together significantly attenuated the risk for MI or death conveyed by elevated depressive symptoms (−36.9%, 95% CI −18.9 to −119.1%), with smoking (−17.6%, 95% CI −6.5% to −56.0%) and physical inactivity (−21.0%, 95% CI −9.7% to −61.1%) having the biggest explanatory roles.
Our findings suggest potential roles for behavioral interventions targeting smoking and physical inactivity in patients with CHD and comorbid depression.
PMCID: PMC3568239  PMID: 23290548
myocardial infarction; depression; death; physical exercise; smoking
12.  Gender Differences in Calls to 9-1-1 During an Acute Coronary Syndrome 
Calling 9-1-1 during an acute coronary syndrome (ACS) decreases time to treatment and may improve prognosis. Women may have more atypical ACS symptoms compared to men, but few data are available on differences in gender and ACS symptoms in calling 9-1-1. We conducted patient interviews and structured chart reviews to determine gender differences in calling 9-1-1. Calls to 9-1-1 were assessed by self-report and validated by medical chart review. Of the 476 patients studied, 292 (61%) patients were diagnosed with unstable angina (UAP) and 184 (39%) patients were diagnosed with a myocardial infarction (MI). Overall, only 23% of patients called 9-1-1. A similar percentage of women and men with UAP called 9-1-1 (15% and 13%, respectively, P = 0.59). In contrast, women with MI were significantly more likely to call 9-1-1 than men (57% vs. 28%, P < 0.001). After adjustment for sociodemographic factors, health insurance status, history of MI, left ventricular ejection fraction, GRACE score and ACS symptoms, women were 1.79 times more likely to call 9-1-1 during an MI than men (prevalence ratio 1.79; 95% C.I. 1.22 – 2.64, P < 0.01). In conclusion, the findings in the current study suggest that initiatives to increase calls to 9-1-1 are needed for both women and men.
PMCID: PMC3715374  PMID: 23040599
Acute Coronary Syndrome; Gender; Emergency Services
13.  The Contributions of Unhealthy Lifestyle Factors to Apparent Resistant Hypertension: Findings from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Journal of hypertension  2013;31(2):10.1097/HJH.0b013e32835b6be7.
Unhealthy lifestyle factors may contribute to apparent treatment resistant hypertension (aTRH). We examined associations of unhealthy lifestyle factors with aTRH in individuals taking antihypertensive medications from three or more classes.
Participants (n=2,602) taking three or more antihypertensive medication classes were identified from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. aTRH was defined as having systolic/diastolic blood pressure ≥140/90 mmHg despite the use of three or more antihypertensive medication classes or the use of four or more classes to achieve blood pressure control. Lifestyle factors included obesity, physical inactivity, current smoking, heavy alcohol consumption, a low DASH diet score and high sodium-to-potassium (Na/K) intake.
Among participants taking three or more antihypertensive medication classes, 1,293 (49.7%) participants had aTRH. The prevalence of unhealthy lifestyle factors in participants with and without aTRH was 55.2% and 51.7% respectively for obesity, 42.2% and 40.5% for physical inactivity, 11.3% and 11.5% for current smoking, 3.1% and 4.0% for heavy alcohol consumption, 23.1% and 21.5% for low DASH diet score, and 25.4% and 24.4% for high Na/K intake. After adjustment for age, sex, race, and geographic region of residence, none of the unhealthy lifestyle factors was associated with aTRH. The associations between each unhealthy lifestyle factor and aTRH remained non-significant after additional adjustment for education, income, depressive symptoms, total calorie intake, and co-morbidities.
Unhealthy lifestyle factors did not have independent associations with aTRH among individuals taking three or more antihypertensive medication classes.
PMCID: PMC3838894  PMID: 23303356
Hypertension; blood pressure; antihypertensive agents; epidemiology
14.  Prevalence and Characteristics of Anergia (Lack of Energy) in Patients with Acute Coronary Syndrome 
The American journal of cardiology  2012;110(9):1213-1218.
Anergia, a commonly occurring syndrome in older adults and patients with cardiovascular diseases, is associated with functional and clinical limitations. To date, the prevalence and clinical-demographic characteristics of anergia in patients with acute coronary syndrome (ACS) have not been elucidated. We examined the prevalence and clinical-demographic characteristics of anergia in a multiethnic sample of patients with ACS. Hospitalized patients with ACS (n = 472), enrolled in the Prescription Usage Lifestyle and Stress (PULSE) prospective cohort study, completed assessments of demographic, behavioral, and clinical characteristics within 7 days of hospitalization for an ACS event. Current depressive disorder was ascertained using a structured psychiatric interview 3 to 7 days post-discharge. Anergia was assessed at baseline and defined using patients’ binary responses (yes/no) to seven items related to energy level. At least 1 complaint of anergia was reported by 79.9% (n = 377) of patients, and 32% (n = 153) of patients met criteria for anergia. In a multivariable logistic regression model, anergia was independently associated with being female, white (compared to black), having bodily pain, participating in exercise, having current depressive disorder, and having higher values on the Charlson comorbidity index. In conclusion, anergia is a highly prevalent syndrome among patients with ACS. It is distinct from depression and is associated with modifiable clinical factors such as participation in exercise and bodily pain that may be appropriate targets for intervention.
PMCID: PMC3470778  PMID: 22835409
anergia; acute coronary syndrome; signs and symptoms
15.  Prevalence and correlates of low medication adherence in apparent treatment resistant hypertension 
Low medication adherence may explain part of the high prevalence of apparent treatment resistant hypertension (aTRH). We assessed medication adherence and aTRH among 4,026 participants taking ≥ 3 classes of antihypertensive medication in the population-based REGARDS Study using the 4-item Morisky Medication Adherence Scale (MMAS). Low adherence was defined as a MMAS score ≥ 2. Overall, 66% of participants taking ≥ 3 classes of antihypertensive medication had aTRH. Perfect adherence on the MMAS was reported by 67.8% and 70.9% of participants with and without aTRH, respectively. Low adherence was present among 8.1% of participants with aTRH and 5.0% of those without aTRH (p<0.001). Among those with aTRH, female gender, residence outside the US stroke belt or stroke buckle, physical inactivity, elevated depressive symptoms, and a history of coronary heart disease were associated with low adherence. In the current study, a small percentage of participants with aTRH had low adherence.
PMCID: PMC3464920  PMID: 23031147
Hypertension; Treatment Resistant Hypertension; Medication adherence; Risk Factors
16.  Association between Annual Visit-to-Visit Blood Pressure Variability and Stroke in Postmenopausal Women: Data from the Women's Health Initiative 
Hypertension  2012;60(3):625-630.
Accumulating evidence suggests that increased visit-to-visit variability (VVV) of blood pressure is associated with stroke. No study has examined the association between VVV of blood pressure and stroke in postmenopausal women, and scarce data exists as to whether this relation is independent of the temporal trend of blood pressure. We examined the association of VVV of blood pressure with stroke in 58,228 postmenopausal women enrolled in the Women's Health Initiative. Duplicate blood pressure readings, which were averaged, were taken at baseline and at each annual visit. VVV was defined as the standard deviation about the participant's mean systolic blood pressure (SBP) across visits (SD), and about the participant's regression line with SBP regressed across visits (SDreg). Over a median follow-up of 5.4 years, 997 strokes occurred. In an adjusted model including mean SBP over time, the hazard ratios (95% CI) of stroke for higher quartiles of SD of SBP compared to the lowest quartile (referent) were 1.39 (1.03-1.89) for quartile 2, 1.52 (1.13-2.03) for quartile 3, and 1.72 (1.28-2.32) for quartile 4 (P trend<0.001). The relation was similar for SDreg of SBP quartiles in a model that additionally adjusted for the temporal trend in SBP (P trend<0.001). The associations did not differ by stroke type (ischemic vs. hemorrhagic). There was a significant interaction between mean SBP and SDreg on stroke with the strongest association seen below 120 mmHg. In postmenopausal women, greater VVV of SBP was associated with increased risk of stroke, particularly in the lowest range of mean SBP.
PMCID: PMC3427141  PMID: 22753206
hypertension; blood pressure; stroke; postmenopause; women
Hypertension  2012;59(6):1157-1163.
Nighttime blood pressure (BP) dipping can be quantified as the ratio of mean nighttime (sleep) BP to mean daytime (awake) BP. People whose dipping ratio is 0.90 have been referred to as nondippers, and nondipping is associated with cardiovascular disease events. We examined the relationship between systolic nighttime BP dipping in young adults and presence of coronary artery calcium (CAC) 10-15 years later using data from the ambulatory BP monitoring substudy of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among 239 participants with adequate measures of both nighttime and daytime readings and coronary artery calcium, the systolic BP dipping ratio ranged from 0.72 to 1.24 (mean 0.88, SD 0.06), and CAC was present 10 to 15 years later in 54 participants (22.6%). Compared to those whose systolic BP dipping ratio ranged from 0.88 to 0.92 (Quartile 3), the 57 participants (23.9%) with less pronounced or absent dipping (ratio 0.92 to 1.24, Quartile 4) had an unadjusted odds ratio of 4.08 (95% CI 1.48-11.2) for presence of CAC. The 60 participants (25.1%) with a more pronounced dipping (ratio 0.72 to 0.85, Quartile 1) also had greater odds for presence of CAC (OR 4.76; 95% CI 1.76-12.9). When modeled as a continuous predictor, a U-shaped relationship between systolic BP dipping ratio and future CAC was apparent, and persisted after adjustment for multiple potential confounders (p<0.001 for quadratic term). Both failure of systolic BP to dip sufficiently and “overdipping” during nighttime may be associated with future subclinical coronary atherosclerosis.
PMCID: PMC3369268  PMID: 22547435
ambulatory blood pressure; diurnal blood pressure; blood pressure dipping; coronary artery calcium; subclinical atherosclerosis
18.  Masked hypertension and prehypertension: diagnostic overlap and interrelationships with left ventricular mass: the masked hypertension study 
American Journal of Hypertension  2012;25(6):664-671.
Masked hypertension (MHT) and prehypertension (PHT) are both associated with an increase in cardiovascular disease (CVD) risk, relative to sustained normotension. This study examined the diagnostic overlap between MHT and PHT, and their interrelationships with left ventricular (LV) mass index (LVMI), a marker of cardiovascular end-organ damage.
A research nurse performed three manual clinic blood pressure (CBP) measurements on three occasions over a 3-week period (total of nine readings, which were averaged) in 813 participants without treated hypertension from the Masked Hypertension Study, an ongoing worksite-based, population study. Twenty-four-hour ambulatory blood pressure (ABP) was assessed by using a SpaceLabs 90207 monitor. LVMI was determined by echocardiography in 784 (96.4%) participants.
Of the 813 participants, 769 (94.6%) had normal CBP levels (<140/90 mm Hg). One hundred and seventeen (15.2%) participants with normal CBP had MHT (normal CBP and mean awake ABP ≥135/85 mm Hg) and 287 (37.3%) had PHT (mean CBP 120–139/80–89 mm Hg). 83.8% of MHT participants had PHT and 34.1% of PHT participants had MHT. MHT was infrequent (3.9%) when CBP was optimal (<120/80 mm Hg). After adjusting for age, gender, body mass index (BMI), race/ethnicity, history of high cholesterol, history of diabetes, current smoking, family history of hypertension, and physical activity, compared with optimal CBP with MHT participants, LVMI was significantly greater in PHT without MHT participants and in PHT with MHT participants.
In this community sample, there was substantial diagnostic overlap between MHT and PHT. The diagnosis of MHT using an ABP monitor may not be warranted for individuals with optimal CBP.
PMCID: PMC3668422  PMID: 22378035
ambulatory blood pressure monitoring; blood pressure; echocardiography; hypertension
19.  Do Different Depression Phenotypes Have Different Risks for Recurrent Coronary Heart Disease? 
Health psychology review  2011;6(2):165-179.
Although research has consistently established that depression and elevated depressive symptoms are associated with an increased risk of acute coronary syndrome (ACS) recurrence and mortality, clinical trials have failed to show that conventional depression interventions offset this risk. As depression is a complex and heterogeneous syndrome, we believe that using simpler, or intermediary, phenotypes rather than one complex phenotype may allow better identification of those at particular risk of ACS recurrence and mortality and may contribute to the development of specific depression treatments that would improve medical outcomes. Although there are many possible intermediary phenotypes, specifiers, and dimensions of depression, we will focus on only two when considering the relation between depression and risk of ACS recurrence and mortality: Inflammation-Induced Incident Depression and Anhedonic Depression. Future research on intermediary phenotypes of depression is needed to clarify which are associated with the greatest risk for ACS recurrence and mortality and which, if any, are benign. Theoretical advances in depression phenotyping may also help elucidate the behavioral and biological mechanisms underlying the increased risk of ACS among patients with specific depression phenotypes. Finally, tests of depression interventions may be guided by this new theoretical approach.
PMCID: PMC3650680  PMID: 23667382
cardiovascular diseases; depressive disorder; depression; acute coronary syndrome; myocardial infarction; phenotype
20.  Endothelin-1 Release and Stimulation of the Inflammatory Cascade: Is Acute Coronary Syndrome Triggered by Watching Spectator Sports? 
PMCID: PMC3628653  PMID: 20170789
emotional stress; atherosclerosis; inflammation; endothelin-1
21.  Relations between QRS|T Angle, Cardiac Risk Factors, and Mortality in the Third National Health and Nutrition Examination Survey (NHANES III) 
The American Journal of Cardiology  2012;109(7):981-987.
On the surface electrocardiogram (ECG), an abnormally wide QRS|T angle reflects changes in regional action potential duration profiles and in direction of repolarization sequence which is thought to increase the risk of ventricular arrhythmia. We investigated the relationship between abnormal QRS|T angle and mortality in a nationally representative sample of individuals without clinically evident heart disease. We studied 7,052 participants ≥ 40 years of age in the Third National Health and Nutrition Examination Survey (NHANES III) with 12-lead ECGs. Individuals with self-report or ECG evidence of a prior myocardial infarction, QRS duration ≥120 msec, or history of heart failure were excluded. Borderline and abnormal spatial QRS|T angle were defined according to sex-specific 75th and 95th percentiles of frequency distributions. All-cause (n=1093 women, n=1191 men) and cardiovascular mortality (n=462 women, n=455 men) over 14 years was assessed through linkage with the National Death Index. In multivariable analyses, abnormal spatial QRS|T angle was associated with an increased hazard ratio (HR) for cardiovascular mortality in women (HR 1.82, 95% CI 1.05-3.14) and men (HR 2.21, 95% CI 1.32-3.68). An abnormal QRS|T angle was also associated with increased multivariable adjusted HRs for all-cause mortality in women (HR 1.30, 95% CI 0.95-1.78) and men (HR 1.87, 95% CI 1.29-2.7). Borderline QRS|T angle was not associated with increased risk for all-cause or cardiovascular mortality. In conclusion, abnormal QRS|T angle, as measured on a 12-lead ECG, was associated with increased risk for cardiovascular and all-cause mortality in this population-based sample without known heart disease.
PMCID: PMC3313000  PMID: 22221946
electrocardiogram; cardiac mortality; QRS|T angle; epidemiology
22.  Predictors of Low Clopidogrel Adherence Following Percutaneous Coronary Intervention 
The American journal of cardiology  2011;108(6):822-827.
Few data are available on factors associated with low adherence or early clopidogrel discontinuation following percutaneous coronary intervention (PCI). Patients (n=284) were evaluated prior to hospital discharge following PCI to identify factors associated with low adherence to clopidogrel 30 days later. Pre-PCI adherence to daily medications was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8) and categorized as low, medium, or high (scores <6, 6 to <8 and 8, respectively). Low adherence to clopidogrel was defined as a MMAS-8 score < 6 (n=21) or having discontinued clopidogrel (n=11), both ascertained during a 30-day post-PCI interview. At 30 days post-PCI, 11% of patients had low adherence to clopidogrel. The odds ratios (95% confidence interval) for low adherence to clopidogrel was 3.78 (1.09 – 13.1), 3.06 (1.36 – 6.87), 2.46 (0.97 – 6.27) and 3.36 (0.99 – 11.4) for patients who reported, prior to PCI, taking smaller doses of medication due to cost, had difficulty filling prescriptions, had difficulty reaching their primary physician and were not comfortable asking their doctor for instructions, respectively. The odds ratios (95% CI) for low clopidogrel adherence following PCI among patients with medium and low, versus high adherence, to daily medications prior to PCI was 6.13 (1.34 – 28.2) and 10.9 (2.46 – 48.7), respectively. The c-statistic associated with pre-PCI MMAS-8 scores for discriminating low clopidogrel adherence at 30 days post-PCI was 0.733 (95% CI: 0.650 – 0.852). Pre-PCI adherence to daily medications may be a useful indicator for identifying patients who will have low clopidogrel adherence following PCI.
PMCID: PMC3586559  PMID: 21741610
Clopidgrel; medication adherence; percutaneous coronary intervention
23.  Posttraumatic stress due to an acute coronary syndrome increases risk of 42-month major adverse cardiac events and all-cause mortality 
Journal of psychiatric research  2011;45(12):1621-1626.
Approximately 15% of patients with acute coronary syndromes (ACS) develop posttraumatic stress disorder (PTSD) due to their ACS event. We assessed whether ACS-induced PTSD symptoms increase risk for major adverse cardiac events (MACE) and all-cause mortality (ACM) in an observational cohort study of 247 patients (aged 25–93 years; 45% women) hospitalized for an ACS at one of 3 academic medical centers in New York and Connecticut between November 2003 and June 2005. Within 1 week of admission, patient demographics, Global Registry of Acute Coronary Events risk score, Charlson comorbidity index, left ventricular ejection fraction, and depression status were obtained. At 1-month follow-up, ACS-induced PTSD symptoms were assessed with the Impact of Events Scale-Revised. The primary endpoint was combined MACE (hospitalization for myocardial infarction, unstable angina or urgent/emergency coronary revascularization procedures) and ACM, which were actively surveyed for 42 months after index event. Thirty-six (15%) patients had elevated intrusion symptoms, 32 (13%) elevated avoidance symptoms, and 21 (9%) elevated hyperarousal symptoms. Study physicians adjudicated 21 MACEs and 15 deaths during the follow-up period. In unadjusted Cox proportional hazards regression analyses, and analyses adjusted for sex, age, clinical characteristics and depression, high intrusion symptoms were associated with the primary endpoint (adjusted hazard ratio, 3.38; 95% confidence interval, 1.27 – 9.02; p= .015). Avoidance and hyperarousal symptoms were not associated with the primary endpoint. The presence of intrusion symptoms is a strong and independent predictor of elevated risk for MACE and ACM, and should be considered in the risk stratification of ACS patients.
PMCID: PMC3210372  PMID: 21807378
posttraumatic stress disorder; psychosocial factors; risk factors; acute coronary syndrome; recurrence; behavioral medicine
24.  Depressive Symptoms Are Not Associated with Leukocyte Telomere Length: Findings from the Nova Scotia Health Survey (NSHS95), a Population-Based Study 
PLoS ONE  2012;7(10):e48318.
Premature shortening of leukocyte telomere length has been proposed as a novel mechanism by which depression may confer increased risk of adverse cardiovascular events. Prior studies demonstrating associations of depression and depressive symptoms with shorter leukocyte telomere length were small, included selected psychiatric outpatients, were based on convenience samples, and/or adjusted for a limited number of possible confounding factors.
Methods and Findings
We examined the associations of depressive symptoms, probable depressive disorder, and specific depressive symptom clusters, as assessed by the Center for Epidemiological Studies—Depression (CES-D) scale, with leukocyte telomere length, measured by using a real-time PCR method, in 2,225 apparently healthy participants from the 1995 Nova Scotia Health Survey population-based study. The mean age was 48.2±18.9 years; 49.9% of participants were female; and the mean CES-D score was 7.4±7.9. The mean telomere length was 5,301±587 base pairs. In an unadjusted model, depressive symptoms were significantly associated with longer leukocyte telomere length (B = 27.6 base pairs per standard deviation increase in CES-D, 95% confidence interval [CI] = 3.1–52.1, p = 0.027). This association was no longer significant after adjustment for age and sex (B = 9.5, 95% CI = −14.6–33.6, p = 0.44) or after further adjustment for body mass index, Framingham risk score and previous history of ischemic heart disease (all p's≥0.37). Neither probable depressive disorder nor specific depressive symptom clusters were independently associated with leukocyte telomere length.
Concurrent depressive symptoms were not associated with leukocyte telomere length in a large, representative, population-based study.
PMCID: PMC3485011  PMID: 23133583
25.  Observed Hostility and the Risk of Incident Ischemic Heart Disease: A Prospective Population Study from the 1995 Canadian Nova Scotia Health Survey 
To examine the relation between hostility and incident ischemic heart disease (IHD) and to determine whether observed hostility is superior to patient-reported hostility for the prediction of IHD in a large, prospective observational study.
Some studies have found that hostile patients have an increased risk of incident IHD. However, no studies have compared methods of hostility assessment, nor considered important psychosocial and cardiovascular risk factors as confounders. Further, it is unknown whether all expressions of hostility carry equal risk, or whether certain manifestations are more cardiotoxic.
We assessed the independent relationship between baseline observed hostility and 10-year incident IHD in 1,749 adults of the population-based Canadian Nova Scotia Health Survey.
There were 149 (8.5%) incident IHD events (140 non-fatal, 9 fatal) during the 15,295 person-years of observation (9.74 events/1000 person-years). Participants with any observed hostility had a greater risk of incident IHD than those without (p=0.02); no such relation was found for patient-reported hostility. After adjusting for cardiovascular (age, sex, Framingham Risk Score) and psychosocial (depression, positive affect, patient-reported hostility, and anger) risk factors, those with any observed hostility had a significantly greater risk of incident IHD (HR 2.06, 95% CI 1.04–4.08, P=0.04).
The presence of any observed hostility at baseline was associated with a two-fold increased risk of incident IHD over 10 years of follow-up. Compared to patient-reported measures, observed hostility is a superior predictor of IHD.
PMCID: PMC3188395  PMID: 21903054
Observed hostility; patient-reported hostility; ischemic heart disease; depression; positive affect

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