Increased carotid intima-media thickness (cIMT) is associated with heart failure (HF) in previous studies, but it is not known whether the association of cIMT differs between HF with reduced (HFrEF) versus preserved ejection fraction (HFpEF). We studied 6699 participants (mean age 62 ± 10 years, 47% male, and 38% white) from the Multi-Ethnic Study of Atherosclerosis (MESA) with baseline cIMT measurements. We classified HF events as HFrEF (EF <50%) or HFpEF (EF ≥ 50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios (HR), and 95% confidence intervals (CI) for the association between the IMT Z-score (measured maximum IMT of Internal Carotid (IC) and Common Carotid (CC) sites as the mean of the maximum IMT of the near and far walls of right and left sides), and incident HFrEF or HFpEF. Models were adjusted for covariates and interim coronary artery disease (CAD) events. A total of 191 HFrEF and 167 HFpEF events occurred during follow-up. In multivariable analysis, each 1 standard deviation increase in the measured maximum IMT (Z-score) was associated with both HFrEF and HFpEF in the unadjusted and demographically adjusted models [HR, 95% CI 1.57 (1.43 to 1.73)] and [HR, 95% CI 1.61 (1.47 to 1.77)] but not in the fully adjusted models [HR, 95% CI 1.11 (0.96 to 1.28)] and [HR, 95% CI 1.13 (0.98 to 1.30)]. In conclusion, cIMT was significantly associated with incident HF, but the association is partially attenuated with adjustment for demographic factors and becomes non-significant after adjustment for other traditional heart failure risk factors and interim CAD events. There was no difference in the association of IMT measures with HFrEF versus HFpEF.
Heart failure (HF) related mortality, morbidity, health care costs, and poor quality of life are major public health problems in the United States as the prevalence and incidence of HF continue to rise. The prevalence and the rates of adverse clinical outcomes for both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) are generally similar. Most studies of cIMT have focused on its relationship with coronary artery disease (CAD). , However, cIMT has been shown to be associated with incident HF. cIMT may be associated with risk of HFrEF due to shared atherosclerotic pathways. , On the other hand, cIMT may be associated with HFpEF through mechanisms other than myocardial ischemia or infarct. For instance, an increase in cIMT is associated with a decrease in arterial distensibility, which in turn leads to increased pressure afterload, pressure wave propagation, and diastolic dysfunction. , Therefore, utilizing data from MESA we studied the association between cIMT and HF both overall and stratified by HFrEF versus HFpEF. We also studied the relationship between ICA versus CCA IMT with HFrEF and HFpEF ( Figure 1 ).
Methods
MESA is a multi-ethnic, multicenter, prospective observational cohort of 6,814 men and women aged 45 to 84 years without clinical CVD at baseline (participation rate was 60% among those eligible), who were recruited between July 2000 and August 2002 from 6 US communities (Forsyth county, NC, Baltimore, MD, Chicago, IL, Los Angeles County, CA, northern Manhattan, NY; and St. Paul, MN). All participants provided written informed consent and the study was approved by the institutional review boards at all field centers. For this analysis, participants (N = 88) were excluded if they were missing baseline cIMT data.
Participant’s characteristics were collected during the initial MESA visit. Age, sex, race/ ethnicity, and education were self-reported. Education was categorized as high school or less or some college or more. Smoking was defined as ever (current or former) versus never smoker. Blood samples were obtained after a 12-hour fast, and measurements of total cholesterol, high-density lipoprotein cholesterol, and plasma glucose were used. Diabetes mellitus was defined as fasting glucose values ≥ 126 mg/dl or a history of diabetes medication use. Blood pressure was measured for each participant after 5 minutes in the seated position, and systolic measurements were recorded 3 separate times, and the mean of the last 2 values was used. The use of aspirin, statins, and antihypertensive medications was collected by medication inventory. Body mass index was computed as the weight in kilograms divided by the square of height in meters. Resting heart rate was obtained from baseline ECGs.
The participants were imaged supine with their head rotated 45 degrees away from the side being imaged, and the images were recorded on superVHS videotape. The CCA was imaged at 45 degrees from the vertical with the beginning of the bulb shown to the left of the image. The ICA was imaged in three projections centered on the ICA flow divider: anterior, lateral (at 45 degrees), and posterior. A matrix array probe (M12L, General Electric, Waukesha, WI) was used. cIMT was measured on near and far walls of the common carotid (1 projection) and the ICA (3 projections) using hand-drawn continuous tracings of the intima-lumen and media-adventitia interfaces that were then processed using a previously described algorithm. The average of the mean far wall CC IMT and the maximum of the near and far wall IC IMT values seen on either side or projection were used for these analyses and it was consistent with prior studies. ,
In addition, we created a composite Z score for overall maximal IMT by summing the maximum IMT from the two carotid IMT sites (right and left if both were measured) after standardization (subtraction of the mean and division by standard deviation of each measure), and then dividing by the standard deviation of the sum. If only one of the two measures were available, it was used. The resulting variable is hereafter referred to as Z score maximum IMT.
The ascertainment of incident HF events in MESA has been described previously. Participants were contacted by telephone every 9 to 12 months or at MESA follow up examinations and data obtained for interim hospitalizations, outpatient diagnoses and deaths from baseline through December 31, 2013. Two physicians reviewed each record for independent endpoint classification and assignment of event dates. Incident HF was defined as including symptoms of HF, a physician diagnosis of HF, and another objective feature of HF (dilated or poor LV function, pulmonary edema by chest radiograph, heart failure treatment, or evidence of diastolic dysfunction). HF events were identified per the MESA events committee and they provide information on EF. HFpEF events were defined as cases with ejection fraction ≥50% per ACC/AHA guidelines, which classify patients with a LVEF of ≥50% as having a preserved EF. Comprehensive statistics were performed to characterize the data, and baseline characteristics were compared by HF status. Categorical variables were reported as frequency and percentage, whereas continuous variables were recorded as mean ± SD. Statistical significance for categorical variables was tested using χ² method and the ANOVA procedure for continuous variables.
Follow-up time was defined as the time between the baseline cIMT measurement until a diagnosis of HF, death, loss to follow-up, or end of study follow-up (December 31, 2013). Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CI) for the association of each CCA IMT and ICA IMT measurement with HF. P values for the HRs were computed using the likelihood ratio method. Separate analyses were conducted for HFrEF and HFpEF outcomes. In another set of analyses, Cox regression was used to compute HRs and 95% CI for the association between Z-score for maximal IMT with HF total, HFrEF and HFpEF ( Figure 2 ), in which Z-score for maximal IMT (measured maximum IMT of the ICA and CCA sites) of the near and far walls of the right and left sides. A sequence of nested multivariable models were constructed as follows: model 1 adjusted for age, sex and race/ethnicity; model 2 adjusted for model 1 covariates plus body mass index (BMI), diabetes mellitus (DM), systolic blood pressure, left ventricular hypertrophy and heart rate; model 3 adjusted for model 1 and model 2 covariates in addition to interim CAD events. The Fine-Gray model was used to account for competing risk of developing HFrEF and HFpEF. This method allowed us to model time to first HF with either HFrEF or HFpEF as the main event of interest and the alternative as the competing risk. This method allowed mutual exclusivity of the classification of HF event types. Statistical significance was defined as p <0.05 SAS version 9.4 (Cary, NC, United States) was used for all analyses.
Results
A total of 6699 participants (mean age 62 ± 10 years, 47% male, 38% whites, 20% blacks, 24% Hispanics, 14% Chinese American) were included in the final analysis. Over a median follow-up of 12.1 years, a total of 385 HF cases (incidence rate per 1000 person-years: 4.16) were identified. Of these, 191 (50%) were HFrEF and 167 (43%) were HFpEF. Baseline characteristics stratified by the development of HF are shown in Table 1 . As shown, participants who did not develop HF were more likely to be younger, to be female, to have higher educational attainment, and to have fewer cardiovascular risk factors than those who developed HFrEF or HFpEF. Participants with incident HFpEF were more likely to be older, to be female, to report smoking, and to have higher systolic blood pressure and resting heart rate than participants with incident HFrEF.
| No heart failure (N = 6341) | HFrEF (N = 191) | HFpEF (N = 167) | p value | |
|---|---|---|---|---|
| Age (years) | 61.8 +/- 10.2 | 67.2 +/- 9.0 | 61.8 +/- 10.2 | <0.001 |
| Men | 2952 (46.6%) | 128 (67.0%) | 78 (46.7%) | <0.001 |
| <0.001 | ||||
| White | 2436 (38.4%) | 73 (38.2%) | 74 (44.3%) | 0.001 |
| Chinese | 773 (12.2%) | 5 (2.6%) | 17 (10.2%) | |
| Black | 1732 (27.3%) | 72 (37.7%) | 43 (25.8%) | |
| Hispanic | 1400 (22.1%) | 41 (21.5%) | 33 (19.8%) | |
| Education, high school or less | 5205 (82.3%) | 151 (79.5%) | 127 (76.1%) | 0.07 |
| Body mass index (kg/m 2 ) | 28.2 +/- 5.4 | 29.3 +/- 5.3 | 30.2 +/- 6.2 | <0.001 |
| Diabetes mellitus | 742 (11.7%) | 53 (27.8%) | 44 (26.4%) | <0.001 |
| Total cholesterol (mg/dL) | 194.4 +/- 35.9 | 189.4 +/- 35.0 | 189.5 +/- 33.5 | 0.04 |
| Low-density lipoprotein cholesterol (mg/dL) | 117 +/- 31 | 114 +/- 32 | 112 +/- 29 | 0.079 |
| High-density lipoprotein cholesterol (mg/dL) | 51.1 +/- 14.9 | 47.3 +/- 13.0 | 49.9 +/- 13.7 | 0.002 |
| Lipid-lowering medication use | 1010 (15.9%) | 41 (21.5%) | 32 (19.2%) | 0.07 |
| Healthy diet * | 2858 (47.0%) | 85 (47.8%) | 84 (52.2%) | 0.42 |
| Systolic blood pressure (mmHg) | 126.9 +/- 21.2 | 137.0 +/- 22.7 | 139.3 +/- 22.9 | <0.001 |
| Heart rate (beat-per-minute) | 63.0 +/- 9.6 | 63.3 +/- 10.7 | 65.4 +/- 9.8 | 0.001 |
| Glomerular Filtration Rate (mL/min/1.73m 2 ) | 74.6 +/- 16.3 | 70.9 +/- 19.2 | 71.3 +/- 19.3 | <0.001 |
| Left Ventricular Hypertrophy | 54 (0.86%) | 7 (3.7%) | 54 (0.86%) | <0.001 |
| Anti-hypertensive medication use | 2261 (36.0%) | 112 (58.6%) | 98 (58.7%) | <0.001 |
| Family history of coronary heart disease | 2516 (42.3%) | 91 (51.7%) | 69 (44.0%) | 0.04 |
| Cigarette smoking | ||||
| Never | 3217 (50.9%) | 80 (42.1%) | 72 (43.1%) | |
| Former | 2281 (36.1%) | 81 (42.6%) | 78 (46.7%) | |
| Current | 824 (13.0%) | 29 (15.3%) | 17 (10.2%) | |
| Alcohol use | <0.001 | |||
| Never | 1302 (20.7%) | 27 (14.2%) | 33 (19.8%) | |
| Former | 1469 (23.3%) | 64 (33.7%) | 58 (34.7%) | |
| Current | 3525 (56.0%) | 99 (52.1%) | 76 (45.5%) | |
| Internal Carotid IMT (mm) | 1.1 +/- 0.59 | 1.3 +/- 0.71 | 1.4 +/- 0.73 | <0.001 |
| Common Carotid IMT (mm) | 0.87 +/- 0.19 | 0.95 +/- 0.21 | 0.95 +/- 0.18 | <0.001 |
| Z- Score Maximum IMT | -0.025 +/- 0.989 | 0.487 +/- 1.099 | 0.512 +/- 1.025 | <0.001 |
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