Serum Levels of Homocysteine and Circulating Antioxidants Associated with Heart Rate Variability in Patients with Unstable Angina Pectoris
Unstable angina pectoris (UAP) is a critical condition in cardiovascular medicine, characterized by unpredictable chest pain that can occur at rest or with minimal exertion. It is a manifestation of acute coronary syndrome and is associated with a high risk of myocardial infarction and sudden cardiac death. Autonomic dysfunction, which involves the imbalance of the sympathetic and parasympathetic nervous systems, plays a significant role in the pathogenesis of UAP. This dysfunction can lead to impaired coronary artery function, coronary spasm, and increased myocardial ischemia, ultimately lowering the threshold for ventricular fibrillation and elevating the risk of sudden cardiac death.
Oxidative stress, defined as the excessive production of reactive oxygen species (ROS) that overwhelms the body’s antioxidant defenses, has been implicated in the initiation and progression of cardiovascular diseases. Although the precise relationship between autonomic dysfunction and oxidative stress remains unclear, oxidative stress is believed to contribute to neurodegenerative diseases through mechanisms such as excitotoxicity, neuronal loss, and axonal impairment. In the context of cardiovascular diseases, oxidative stress has been linked to autonomic dysfunction, particularly in conditions like diabetes and hypertension.
Heart rate variability (HRV) is a non-invasive measure that reflects the fluctuations in the autonomic nervous system. It is widely used to assess autonomic function in both healthy individuals and patients with cardiovascular disorders. Reduced HRV has been associated with increased oxidative stress in hypertensive and prehypertensive patients. However, the relationship between HRV and circulating oxidative-antioxidant substances in patients with unstable angina has not been thoroughly investigated.
This study aimed to explore the correlation between HRV and circulating oxidative-antioxidant substances, including homocysteine (Hcy), albumin, uric acid, and bilirubin, in patients with unstable angina. The study included 216 consecutive Chinese patients admitted to the Affiliated Hospital of Shandong University of Traditional Chinese Medicine with a diagnosis of unstable angina between February 1, 2015, and May 1, 2017. Patients were diagnosed with unstable angina if they exhibited at least one of the following features: angina at rest lasting more than 20 minutes, new-onset angina of at least Canadian Cardiovascular Society class III severity within one month, or previously diagnosed angina that had become more frequent, longer in duration, or lower in threshold. Patients with conditions such as hemodynamically unstable valvular heart disease, recent acute myocardial infarction, persistent atrial fibrillation, severe heart conduction disorders, acute heart failure, abnormal hepatic or renal function, recent gout, severe respiratory illness, malignant tumors, connective tissue diseases, recent surgery, or infectious diseases were excluded. Ultimately, 190 patients were enrolled in the study.
The study collected demographic, biochemical, and HRV data from the medical records of the eligible patients. HRV was assessed using the standard deviation of all NN intervals (SDNN), with patients classified into two groups based on a cutoff of 100 ms: those with suppressed HRV (SDNN <100 ms) and those with normal HRV (SDNN ≥100 ms). The clinical characteristics of the two groups were compared using Student's t-test for continuous variables and chi-square tests for categorical variables. Univariate correlation analysis was performed using Pearson or Spearman correlation tests, and multivariate linear regression analysis was conducted to identify associations between HRV parameters and serum levels of Hcy and circulating antioxidants. Binary logistic regression analysis was used to identify significant independent factors related to suppressed HRV.
The results showed that patients with suppressed HRV were significantly older and had higher heart rates compared to those with normal HRV. Additionally, patients with suppressed HRV had lower levels of high-density lipoprotein cholesterol (HDL-C), albumin, and direct bilirubin, and higher levels of hemoglobin A1c, serum creatinine, urea nitrogen, uric acid, and Hcy. They were also more likely to have chronic heart failure. Univariate correlation analysis revealed that SDNN was positively correlated with serum albumin levels and negatively correlated with Hcy levels. The square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD) was positively correlated with serum albumin and direct bilirubin levels. The natural logarithm of low-frequency power (Ln LF) was also positively correlated with serum albumin and direct bilirubin levels.
Multivariate linear regression analysis, after adjusting for confounding variables, confirmed that SDNN remained positively correlated with albumin levels and inversely correlated with Hcy levels. SDNN was also associated with hemoglobin A1c, systolic blood pressure (SBP), and chronic heart failure. RMSSD was positively correlated with HDL-C, direct bilirubin, albumin, and age, while it was inversely correlated with a history of hypertension. Binary logistic regression analysis identified decreased albumin levels, increased Hcy levels, and elevated hemoglobin A1c as independent predictors of suppressed HRV.
Homocysteine, a demethylated metabolite of the essential amino acid methionine, is known to exacerbate neurotoxicity through oxidative stress. Elevated Hcy levels have been linked to autonomic neuropathy, and this study found that increased Hcy levels were inversely correlated with SDNN, suggesting that Hcy could be an indicator of depressed HRV in patients with unstable angina. This relationship may be explained by the direct neurotoxicity of Hcy and the indirect effects of Hcy-induced atherosclerosis on blood supply.
Albumin, the primary extracellular molecule responsible for maintaining the plasma redox state, has antioxidant properties that limit ROS production and scavenge ROS. In patients with type 2 diabetes, serum albumin has been associated with the severity of neuropathy. This study found that decreased albumin levels were inversely correlated with SDNN and RMSSD, indicating that reduced albumin levels might reflect autonomic dysfunction in unstable angina patients.
Bilirubin, the end product of heme catabolism, is recognized as an endogenous antioxidant and anti-inflammatory molecule. Elevated bilirubin levels have been associated with a reduced risk of cardiovascular diseases, hypertension, diabetes, and metabolic syndrome. In type 2 diabetic patients, higher bilirubin levels are inversely associated with the prevalence of cardiovascular autonomic neuropathy. This study found that direct bilirubin levels were positively correlated with RMSSD, suggesting that higher bilirubin levels may enhance parasympathetic activity in unstable angina patients. However, excessively high bilirubin levels can be neurotoxic, indicating that the relationship between bilirubin and autonomic function is complex.
In conclusion, this study highlights the association between circulating oxidative-antioxidant substances and HRV in patients with unstable angina. Specifically, decreased levels of albumin and increased levels of Hcy and hemoglobin A1c were identified as independent predictors of suppressed HRV. These findings suggest that these laboratory parameters, along with HRV, could be useful in diagnosing cardiac autonomic neuropathy in patients with unstable angina. The study underscores the importance of oxidative stress and autonomic dysfunction in the pathophysiology of unstable angina and provides insights into potential biomarkers for assessing autonomic function in these patients.
doi.org/10.1097/CM9.0000000000000007
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