Elevated level of antibodies to oxidized low-density lipoproteins (OxLDL-Ab) was shown to reliably predict morbidity and mortality in patients with heart failure (HF). Two hundred and eleven patients aged ≥65 years treated at the Heart Failure Unit, Tel Aviv-Sourasky Medical Center, were included in this retrospective study. The end points were time to the first hospitalization (morbidity), all-cause mortality, and a combination of the two (composite outcome). HF duration ranged from 8 to 10.5 years. Mean follow-up was 5.2 ± 1.9 years. The mean number of clinical visits was 18.3 ± 2.4. Participants were divided according to OxLDL-Ab level. Group 1 had Ox LDL-Ab level <200 arbitrary U/ml. Group 2 had OxLDL-Ab level ≥200 arbitrary U/ml. The mean time to the first hospitalization was 25.8 ± 17.0 months. The mortality rate was 44.1%. Combined mortality and hospitalization rate was 58.8%. Adjusted hazard ratios of OxLDL-Ab for hospitalization were 3.16, p <0.001, 95% confidence interval 1.740 to 5.736 and for composite outcome 2.67, p <0.001, 95% confidence interval 1.580 to 4.518. In conclusion, OxLDL-Ab level was the best predictor for both hospitalization and composite outcome. It may, thus, serve as a useful clue for early and more accurate detection of poorly controlled HF and as a marker for imminent exacerbations of thereof.
There is considerable evidence that oxidative stress is increased in both ischemic and nonischemic cardiomyopathies. Oxidized low-density lipoprotein (OxLDL) is present in atheromatous plaque and correlates with the extent of atherosclerosis and heart failure (HF). This together with the inverse relation between OxLDL plasma level and left ventricular ejection fraction (LVEF) supported the assumption that plasma levels of OxLDL have value in predicting mortality in patients with HF. Steinerova et al suggested that assessment of antibodies to OxLDL (OxLDL-Ab) may reliably reflect the level of oxidative stress. Those antibodies have already been shown to correlate with the extent of atherosclerosis and to predict future myocardial infarction. Oxidative stress has been reported to increase in subjects aged ≥65 years, possibly arising from an uncontrolled production of free radicals by aging mitochondria and decreased antioxidant defenses. The aim of this study was to assess the potential applicability of OxLDL-Ab levels in predicting morbidity, mortality, and the composite outcome of the two in a cohort of patients with chronic HF who were aged ≥65 years.
Methods
Medical records of all the patients aged ≥65 years who were admitted to the Heart Failure Outpatient Unit at the Tel Aviv-Sourasky Medical Center (Tel Aviv, Israel) from January 2000 through July 2001 because of chronic HF were reviewed, and pertinent data were included in the present retrospective study after obtaining signed informed consent. Systolic HF was defined as LVEF ≤40% by echocardiography or by Tc 99 ventriculography. Data retrieved from the medical records included medical history, current and past medications, resting blood pressure, heart rate, weight, and New York Heart Association (NYHA) class (based on the retrieved information, echocardiography, or isotopic ventriculography). Excluded from the study were patients who had malignant disease, cerebral vascular disease, inflammatory disorder, and connective tissue disease or infections as well as those who were chronically bedridden and those who lacked sufficient follow-up information. At the first visit, blood was sampled for routine biochemistry values and for OxLDL-Ab. Patients were examined at least every 3 months throughout the follow-up period. The end points of the study were time to the first hospitalization, all-cause mortality, and a combination of the two (which was referred to as composite outcome). The study was approved by the ethical committee of the Tel Aviv- Sourasky Medical Center.
To measure the OxLDL-Ab level of the study participants, a single batch of OxLDL-Ab and native LDL and OxLDL was prepared from the plasma of 20 healthy donors as previously described.
Statistical analysis
Categorical variables were reported as numbers (percentages), and continuous variables as means (±standard deviations [SD]) or medians and interquartile ranges (IQR). Continuous variables were tested for normal distribution using the Kolmogorov–Smirnov test and Q-Q Plots. The OxLDL-Ab level was divided into tertiles and the upper tertile (group 2) was compared to the 2 lower tertiles (group 1) with a cut-off point of OxLDL-Ab level at 200 arbitrary U/ml. Baseline categorical variables were compared between the upper OxLDL-Ab level tertile and the lower tertiles using the chi-square test or Fisher’s exact test, and continuous variables by the independent samples t test or by the Mann–Whitney test. The multivariate Cox regression was used to evaluate the association between the OxLDL-Ab upper tertile level and outcomes while controlling for potential confounders. A forward stepwise likelihood ratio method was used for this purpose. A 2-tailed p value <0.05 was considered statistically significant. Analyses were performed with SPSS version 21.
Results
A total of 239 patients aged ≥65 years with chronic HF were evaluated for analysis in this retrospective study. Of them, 28 were excluded for noncompliance or lack of sufficient follow-up information ( Figure 1 ). The remaining 211 patients were entered into the study analysis. Salient characteristics are listed in Table 1 . Severe HF duration ranged from 8 months to 10.5 years before January 2000. The mean number of clinical visits was 18.3 ± 2.4. The mean follow-up time was 5.2 ± 1.0 years. For better indication of OxLDL-Ab predictive value, we divided the values of OxLDL level into tertiles. Tertile 1 was >200 arbitrary units and tertile 2 and 3 below that value. However, there were no significant differences between tertile 2 and 3, and they were grouped together. Therefore, participants were divided into group 1 with an OxLDL-Ab level <200 U/ml and group 2 with an OxLDL-Ab level ≥200 U/ml. There were no differences in age, NYHA class, LVEF, mortality, morbidity, and combined outcome or underling disease ( Table 1 ) between groups 1 and 2. Sixty-seven percent of patients in group 1 and 38.3% of patients in group 2 had at least 1 episode of atrial fibrillation during the follow-up period. This, however, did not reach statistical significance and did not affect the predicting power of OxLDL-Ab level in the respective groups.
| Variable | Total Cohort (n = 211) | Oxidized LDL- Ab | P | |
|---|---|---|---|---|
| <200 (n = 142 ) | ≥200 (n = 69) | |||
| Age (years) | 76.7 | 77.2 | 76.1 | 0.15 |
| Range (years) | 65-96 | |||
| Weight (kg) | 74.4 | 74.4 | 74.6 | 0.9 |
| Males | 154 (73%) | 96 (60.5%) | 58 (80.4%) | 0.83 |
| Females | 57 (27%) | 46 (39.5%) | 11 (19.6%) | 0.73 |
| NYHA Class | 2.8 | 2.8 | 2.8 | 0.95 |
| LVEF | 38.(5%) | 36.0 | 39.7 | 0.79 |
| LVEF <40% | 127 (60.2%) | 88 (61.9%) | 39 (56.55%) | 0.65 |
| Hospitalization | 81 (38.4%) | 49 (34.5%) | 32 (46.4%) | 0.40 |
| Mortality | 93 (44.1%) | 58 (40.8%) | 35 (50.7%) | 0.45 |
| Hospitalization plus Mortality | 124 (58.8%) | 45 (55.6%) | 79 (65.2%) | 0.42 |
| Hyperlipidemia | 125 (59.2%) | 81 (64.8%) | 44 (35.2%) | 0.35 |
| Smoking | 56 (26.5%) | 35 (62.5%) | 21 (37.5%) | 0.37 |
| Hypertension | 134 (63.5%) | 92 (68.7%) | 42 (31.3%) | 0.58 |
| Diabetes | 87 (41.2%) | 62 (71.3%) | 25 (28.7%) | 0.30 |
| Ischemic heart disease | 181 (90.5%) | 131 (68.6%) | 60 (31.4%) | 0.22 |
| Valvular disease | 44 (20.9%) | 26 (59.1%) | 18 (40.9%) | 0.19 |
| Chronic atrial fibrillation | 60 (28.4%) | 37 (61.7%) | 23 (38.3%) | 0.27 |
| Stroke | 34 (16.1%) | 24 (70.6%) | 10 (29.4%) | 0.66 |
| Percutaneous coronary intervention / coronary bypass graft | 107 (50.7%) | 74 (69.2%) | 33 (30.8%) | 0.56 |
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