Current data suggest that increases in hemoglobin may decrease nitric oxide and adversely affect vascular function. In the preclinical setting, these changes could precipitate the development of heart failure (HF). We hypothesized that higher hematocrit (HCT) would be associated with an increased incidence of new-onset HF in the community. We evaluated 3,523 participants (59% women) from the Framingham Heart Study who were 50 to 65 years old and free of HF. Participants were followed prospectively until an HF event, death, or the end of 20 years of follow up. HCT was subdivided into 4 gender-specific categories (women: HCT 36.0 to 40.0, 40.1 to 42.0, 42.1 to 45.0, >45.0; men: 39.0 to 44.0, 44.1 to 45.0, 45.1 to 49.0, >49.0). Gender-pooled multivariable Cox proportional hazards models were used to estimate the association of HCT with incident HF, adjusting for clinical risk factors. During the follow-up period (61,417 person-years), 217 participants developed HF (100 events in women). There was a linear increase in risk of HF across the 4 HCT categories (p for trend = 0.002). Hazards ratios for HF in the low–normal, normal, and high HCT categories were 1.27 (95% confidence interval 0.82 to 1.97), 1.47 (1.01 to 2.15), and 1.78 (1.15 to 2.75), respectively, compared to the lowest HCT category (p for trend <0.0001). Adjustment for interim development of other cardiovascular diseases and restriction of the sample to nonsmokers did not alter the results. In conclusion, higher levels of HCT, even within the normal range, were associated with an increased risk of developing HF in this long-term follow-up study.
Epidemiologic studies of the relation between hematocrit (HCT) and cardiovascular disease are inconsistent, and there are few data on the association of HCT with the development of heart failure (HF) in the community. We studied the association of HCT and HF in subjects in the Framingham Heart Study because investigating this relation in a primary prevention setting decreases the risk of confounding by active disease. We hypothesized that high HCT, even within the “normal range,” would be associated with a greater risk of new-onset HF.
Methods
The original Framingham Heart Study is a longitudinal cohort study focused on the epidemiology of cardiovascular disease. Subject selection and study design have been described previously. The targeted study population for these analyses included participants who were 50 to 65 years old and subjects were included whenever they first met the age criteria. Thus, the “baseline visit” ranged from biennial examinations 1 through 11. This age range was chosen so the baseline HCT studied would be reasonably proximate to any cardiovascular event.
Of the 5,209 participants enrolled at the first examination of the original cohort, 1,686 were excluded from the analyses because no data were available at ages 50 through 65 years (n = 147), data on HCT were missing (n = 308), follow-up data for HF were missing (n = 3), or data on potential confounders at the time of HCT measurement were missing (n = 789; 465 of whom were missing smoking data). Participants with prevalent HF (n = 34), cancer (n = 74), diabetes mellitus (n = 81), cerebrovascular accident (n = 21), or coronary heart disease (CHD; n = 154) were excluded, as were subjects with anemia (HCT <39 in men, <36 in women, n = 51) or who were underweight (body mass index <18 kg/m 2 , n = 24). The final study sample consisted of 3,523 participants. All participants provided written informed consent and the study protocol was approved by the institutional review board of Boston University Medical Center.
All participants underwent clinical examination, measurement of anthropometry, electrocardiography, and laboratory examination, as described elsewhere. A single HCT (directly measured or converted from hemoglobin values) measured at the baseline examination was used in this study. HCT was measured at examinations 4 through 11 and hemoglobin at examinations 2 through 6. Data for hemoglobin and HCT from examination 4 were used to derive a conversion factor that was then applied to the hemoglobin data from examinations 2 and 3 to estimate HCT level at those examinations. Accuracy of the conversion factor was tested using data for subjects at examinations 5 and 6 as follows: HCT = hemoglobin × 3.2. The mean predicted HCT was virtually identical to the mean measured HCT and all differences between measured and predicted HCT values were very small. In addition, this conversion factor was very similar to that used in a previous study in the same sample. HCT was measured using the Wintrobe method.
Subjects were defined as having hypertension if they had a mean systolic blood pressure of ≥140 mm Hg or a mean diastolic blood pressure of ≥90 mm Hg on 2 consecutive Framingham examinations. In addition, all participants being treated with an antihypertensive medication were considered to have hypertension at the time of first report of such medications. Diabetes mellitus was defined as a fasting blood glucose level >125 mg/dl or use of insulin or oral hypoglycemic medications. Left ventricular hypertrophy was diagnosed based on electrocardiographic assessment. The physical activity index was calculated as the number of self-reported hours per day spent doing moderate or vigorous activities multiplied by a numeric weight derived from the oxygen consumption required (liters per minute) for that activity.
Cigarette smoking is known to cause an increased HCT and is a strong predictor of cardiovascular disease risk. We included total pack-years of smoking as a potential confounder in the multivariable models. Because 461 participants were missing data for pack-years of smoking, we created a series of logical rules for data substitution in these cases. Such data substitution was used for approximately 9% of participants.
The primary end point of this study was incident HF. HF was defined by the presence of 2 major or 1 major and 2 minor criteria for HF (Framingham criteria). Major criteria included paroxysmal nocturnal dyspnea, distended neck veins, rales, increasing heart size or pulmonary edema on chest x-ray, S 3 , increased venous pressure (16 cm of water from the right atrium), and hepatojugular reflex. Minor criteria were bilateral ankle edema, night cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, decrease in vital capacity by 1/3 from maximum recorded, or tachycardia (≥120 beats/min). Data were censored at 20 years of follow-up to minimize the effect of competing risks. Participants were followed until the first occurrence of HF, death, or the end of the 20-year follow-up.
Gender-specific quintiles of HCT were created. Because ranges of HCT in the third and fourth quintiles were narrow, HCT was collapsed into 4 distinct categories for analysis. For women, ranges of HCT within the 4 groups were 36.0% to 40.0% (low), 40.1% to 42.0% (low–normal), 42.1% to 45.0% (normal), and ≥45.1% (high). For men, ranges were 39.0% to 44.0% (low), 44.1% to 45.0% (low–normal), 45.1% to 49.0% (normal), and ≥49.1% (high). These gender-specific cutpoints were retained for all analyses.
Descriptive statistics were used to obtain baseline characteristics in the 4 HCT categories. Incidence of HF curves were created using the Kaplan–Meier method and differences among HCT categories were compared using log-rank test. We used multivariable Cox proportional hazards models to assess the association between baseline HCT and risk of developing HF, with adjustment for the following potential confounders that have been previously associated with HCT and risk of HF: age, gender, education level, body mass index, serum cholesterol, smoking history (pack-years), electrocardiographic left ventricular hypertrophy, prevalent hypertension, and physical activity level.
We developed additional models incorporating time-dependent covariates to test whether associations with HCT were mediated by interim development of hypertension, CHD, cerebrovascular vascular accident (CVA), or diabetes. Definitions of CHD and CVA in the Framingham Heart Study have been described elsewhere. We also repeated our analyses restricted to participants who were lifetime nonsmokers (0 pack-year at baseline examination) to minimize the likelihood of confounding by smoking-induced erythrocytosis.
All analyses were performed with SAS 9.1 (SAS Institute, Cary, North Carolina).
Results
Baseline characteristics of the sample are presented in Table 1 according to HCT category. Fifty-nine percent of participants were women. The average age of participants at baseline examination was 52 years. Subjects in the highest HCT category were younger, had higher systolic (statistically significant only in women) and diastolic blood pressures, higher cholesterol, and a higher prevalence of hypertension.
| Variable | Men | Women | ||||||
|---|---|---|---|---|---|---|---|---|
| Low (n = 384) | Low–Normal (n = 219) | Normal (n = 594) | High (n = 240) | Low (n = 510) | Low–Normal (n = 503) | Normal (n = 727) | High (n = 355) | |
| Age (years) | 53.2 ± 3.7 | 52.3 ± 3.2 | 52.1 ± 3.1 | 51.2 ± 2.4 | 52.9 ± 3.7 | 53.3 ± 3.8 | 52.2 ± 3.2 | 51.9 ± 3.0 |
| p Value | <0.001 | <0.001 | ||||||
| Hematocrit (%) | 42.2 ± 1.5 | 45.0 ± 0 | 47.2 ± 1.1 | 51.4 ± 1.6 | 39.0 ± 1.1 | 41.5 ± 0.5 | 43.9 ± 0.8 | 47.5 ± 1.9 |
| p Value | <0.001 | <0.001 | ||||||
| Body mass index (kg/m 2 ) | 26.2 ± 3.4 | 26.4 ± 3.5 | 26.5 ± 3.4 | 26.7 ± 3.7 | 25.6 ± 3.9 | 26.0 ± 4.3 | 26.1 ± 4.5 | 26.5 ± 5.3 |
| p Value | 0.316 | 0.040 | ||||||
| Systolic blood pressure (mm Hg) | 133 ± 20 | 133 ± 22 | 134 ± 20 | 136 ± 19 | 136 ± 23 | 137 ± 23 | 136 ± 23 | 140 ± 26 |
| p Value | 0.222 | 0.022 | ||||||
| Diastolic blood pressure (mm Hg) | 83 ± 11 | 84 ± 12 | 85 ± 11 | 88 ± 11 | 83 ± 12 | 84 ± 12 | 84 ± 12 | 87 ± 14 |
| p Value | <0.001 | <0.001 | ||||||
| Pack-years smoked (years) | 23.5 ± 22.0 | 23.8 ± 21.9 | 26 ± 22.8 | 27.6 ± 23 | 4.5 ± 9.3 | 4.8 ± 10.1 | 7.0 ± 11.9 | 12.1 ± 15.2 |
| p Value | 0.084 | <0.001 | ||||||
| Serum total cholesterol (mg/dl) | 227 ± 39 | 231 ± 39 | 236 ± 43 | 243 ± 41 | 239 ± 45 | 249 ± 44 | 251 ± 43 | 257 ± 46 |
| p Value | <0.001 | <0.001 | ||||||
| Physical activity index (hours) | 9.5 ± 9.6 | 9.4 ± 10.4 | 9.2 ± 9.5 | 7.2 ± 7.7 | 5.0 ± 5.7 | 4.7 ± 4.9 | 5.2 ± 5.5 | 5.0 ± 5.6 |
| p Value | 0.014 | 0.493 | ||||||
| Education | ||||||||
| Less than high school | 51% | 43% | 41% | 35% | 40% | 43% | 36% | 32% |
| High school | 26% | 26% | 31% | 34% | 34% | 34% | 33% | 36% |
| More than high school | 23% | 32% | 29% | 31% | 26% | 24% | 31% | 32% |
| p Value | 0.003 | 0.013 | ||||||
| Left ventricular hypertrophy | ||||||||
| No electrocardiographic left ventricular hypertrophy | 95.6% | 99.1% | 96.1% | 96.7% | 97.4% | 96.4% | 96.8% | 96.1% |
| Possible electrocardiographic left ventricular hypertrophy | 1.6% | 0.0% | 1.2% | 1.2% | 0.8% | 1.2% | 0.7% | 0.8% |
| Definite electrocardiographic left ventricular hypertrophy | 2.9% | 0.9% | 2.7% | 2.1% | 1.8% | 2.4% | 2.6% | 3.1% |
| p Value | 0.373 | 0.848 | ||||||
| Hypertension | ||||||||
| Baseline | 35% | 34% | 43% | 50% | 34% | 40% | 39% | 47% |
| p Value | <0.001 | 0.001 | ||||||
| Follow-up | 27% | 28% | 26% | 21% | 33% | 29% | 28% | 27% |
| p Value | 0.327 | 0.243 | ||||||
| Occurrence of coexistent diseases during follow-up | ||||||||
| Diabetes mellitus | 6.2% | 7.3% | 8.2% | 10.8% | 4.1% | 5.7% | 4.9% | 9.5% |
| p Value | 0.221 | 0.005 | ||||||
| Coronary heart disease | 18% | 18% | 22% | 20% | 11% | 11% | 13% | 12% |
| p Value | 0.371 | 0.668 | ||||||
| Cerebrovascular disease | 3% | 5% | 5% | 7% | 4% | 3% | 3% | 4% |
| p Value | 0.131 | 0.827 | ||||||
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