Prognostic Value of Calcium and Phosphorus Status in Elderly Heart Disease Patients with Tricuspid Regurgitation
Tricuspid regurgitation (TR) associated with valve disease is a significant medical issue with increasing prevalence and socioeconomic burden. Moderate or severe TR has been linked to an elevated risk of heart failure and mortality. Studies have demonstrated that blood calcium and phosphorus levels significantly impact the human body, particularly the cardiovascular system. Elevated serum calcium levels are considered a risk factor for cardiovascular disease, while moderate dietary calcium intake has been shown to protect against cardiovascular and all-cause mortality, with calcium supplementation reducing mortality in women. Understanding the relationship between calcium, phosphorus, and all-cause mortality in TR patients is crucial for improving treatment strategies. However, current evidence on this relationship is insufficient. This study aimed to explore whether serum calcium, serum phosphorus, albumin-corrected serum calcium (CorCa), or the calcium-phosphorus product (CaP) affect the risk of all-cause mortality in patients with TR.
The patients in this study were selected from the China Elderly Degenerative Valve Disease (China-DVD) study, a nationwide, multicenter, prospective cohort study for elderly patients aged 60 years or above with valvular heart disease (VHD). The baseline measurement of China-DVD was conducted from September to December 2016 at 69 medical centers across China. The study adhered to the Declaration of Helsinki, and the Institutional Review Board at each center approved the study protocol. Written informed consent was obtained from all participants. The China-DVD study included 8929 consecutive patients with moderate or severe native VHD, defined by echocardiography using an integrative approach according to the 2014 American College of Cardiology/American Heart Association guidelines. Patients were followed for one year. The selection criteria for this study included: (1) disease type: TR; (2) echocardiography measurement at baseline; and (3) complete measurements of serum calcium, serum phosphorus, and albumin at baseline. Exclusion criteria were: (1) infective endocarditis; (2) history of prior valve intervention; (3) other types of VHD; and (4) outliers in calcium, phosphorus, or albumin measurements.
A comprehensive two-dimensional transthoracic echocardiography measurement using standard ultrasound systems was performed for all patients. Dimensions of the left ventricle (LV) and left atrium were measured as recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging and indexed to body surface area. Assessment of LV systolic function was performed by left ventricle ejection fraction (LVEF) measurement using the biplane modified Simpson method. To ensure diagnostic accuracy and measurement consistency, verification of images from all sampled centers was performed at the core laboratory of Fuwai Hospital before participant recruitment. Blood samples were drawn, and measurements of calcium, phosphorus, and albumin were performed using a biomedical analyzer.
The endpoint of this study was all-cause mortality. The mortality risk of patients with different CorCa levels was evaluated and compared. Endpoint information was collected through patient visits, medical records, or telephone interviews. Statistical analyses were detailed in the Supplementary Material. The formulas for the CorCa calculation and albumin calculation are as follows: CorCa = Calcium × 4 + 0.8 × (4–albumin); CaP = Calcium × Phosphorus.
A total of 8929 patients with moderate-to-severe VHD were registered in China-DVD, of whom 1527 had TR. A total of 133 patients who did not complete echocardiography measurements were excluded. Another 635 were excluded due to lack of measurement of calcium, phosphorus, or albumin. Furthermore, 49 outliers of calcium, phosphorus, or albumin were excluded. Finally, 710 TR patients were included in this study. Among the 710 included TR patients, the mean age was 72.9 ± 8.1 years (median: 73.0 years), 39.2% (278/710) were <70 years old, and males accounted for 48.7% (346/710). The mean serum calcium concentration was 2.2 ± 0.3 mmol/L. The mean serum phosphorus concentration was 3.5 ± 0.8 mg/dL. The mean CorCa was 8.8 ± 1.1 mg/dL. The mean follow-up time was 273 ± 130 days. During the follow-up, 57 (8%) patients died.
Restricted cubic spline (RCS) models were built to explore whether calcium, CorCa, phosphorus, and CaP influenced the risk of one-year mortality. The results showed a U-shaped association between phosphorus and mortality risk. This U-shaped association existed in TR patients of different sexes and age groups. The infection points were 3.4 mg/dL and 3.6 mg/dL according to the estimated hazard ratio (HR) by the RCS model. Patients were then divided into three subgroups according to infection points: ≤3.4 mg/dL, 3.4–3.6 mg/dL, and ≥3.6 mg/dL. Three Cox models were further built. The base model only adjusted for age and sex. Furthermore, the following confounders were adjusted for: hypertension history, smoking history, history of myocardial disease, history of aortic disease, symptoms, history of CAD, history of previous myocardial infarction, and history of chronic obstructive pulmonary disease. Left atrial size, left ventricular end-diastolic diameter, left ventricular ejection fraction, and history of pulmonary hypertension (PH) were further adjusted in the full model.
The results of the three models were consistent. In the full model, both phosphorus ≤3.4 mg/dL group and ≥3.6 mg/dL group were associated with a significantly increased risk of all-cause mortality (HR = 2.45, 95% confidence interval [CI]: 1.03–5.79 and HR = 2.60, 95% CI: 1.10–6.14, respectively) compared with the reference group (3.4–3.6 mg/dL). This difference in mortality risk among the three phosphorus concentrations was visually demonstrated by Kaplan–Meier survival curves. Adjusted confounding factors in the above full Cox model were also considered, and the differences in mortality risk among the three phosphorus concentrations still existed. Specifically, the survival probability of patients whose phosphorus concentrations were ≤3.4 mg/dL or ≥3.6 mg/dL was significantly lower than that of those whose phosphorus concentrations were within 3.4–3.6 mg/dL.
The RCS model also indicated a U-shaped association between CaP and the risk of all-cause mortality, which existed in TR patients of different sexes and age groups. The infection points of HR estimated by the RCS model were 2.4 mg/dL and 2.8 mg/dL. Then, patients were divided into three subgroups: ≤2.4 mg/dL, 2.4–2.8 mg/dL, and ≥2.8 mg/dL, according to infection points. Three COX models similar to the phosphorus model were further established. The results of the three models were consistent. In the full model, both CaP ≤2.4 mmol2/L2 and CaP ≥2.8 mmol2/L2 were associated with a significantly increased risk of all-cause mortality compared with the reference group (2.4–2.8 mmol2/L2) (HR = 2.83, 95% CI: 1.26–6.35 and HR = 3.03, 95% CI: 1.25–7.32, respectively). The Kaplan–Meier survival curve visually showed the difference in risk of death between the three CaP concentrations. We then adjusted the survival curves considering the influence of confounding factors in the full model, and the results showed that the difference in the risk of death between the three CaP concentrations still existed. The survival probability of patients with CaP concentrations ≤2.4 mmol2/L2 or ≥2.8 mmol2/L2 was significantly lower than that of patients with CaP concentrations 2.4–2.8 mmol2/L2.
Phosphorus control is important in disease management, especially for cardiovascular disease. The more phosphorus values that do not exceed 4.5 mg/dL, the lower the cardiovascular mortality. Chen et al reported that each 1 mmol/L increase in serum phosphorus was 2.56 (95% CI: 1.75–3.74) for all-cause mortality and 2.60 (95% CI: 1.65–4.08) for cardiovascular mortality among patients with CAD. Little attention has been given to the prognostic value of phosphorus in patients with valve diseases. The present study showed that both a lower level and a higher level of serum phosphorus were associated with an increased all-cause mortality risk compared with TR patients whose serum phosphorus levels were within 3.4–3.6 mg/dL. The mechanisms are unclear, and it has been reported that elevated levels of serum phosphorus are associated with vascular stiffness and endothelial dysfunction, which leads to poor cardiovascular outcomes.
The number of studies exploring the association between CaP concentration and mortality risk in TR patients is limited. Although causality remains to be proven, abundant epidemiologic data imply correlations between CaP and mortality risk. Kim et al reported that CaP concentration might be considered a risk factor for coronary artery disease. The present study revealed that CaP also had a U-shaped association with all-cause mortality in moderate-to-severe TR patients. Specifically, when CaP was ≤2.4 mmol2/L2 or ≥2.8 mmol2/L2, the risk of all-cause mortality increased 2.83 times and 3.03 times, respectively, compared to patients with CaP between 2.4 mmol2/L2 and 2.8 mmol2/L2. Based on the present study, patients whose CaP levels were within 2.4–2.8 mmol2/L2, equal to 29.7–34.7 mg2/dL2, had the smallest all-cause mortality risk.
The strengths of the present study included the prospective longitudinal cohort study design and the standardized measurements of echocardiography, calcium, and albumin. Most importantly, we identified the specific reference values for phosphorus and CaP, providing a clear reference for patients and physicians to reduce the risk of all-cause mortality in TR patients. In summary, there was a U-shaped association between phosphorus and all-cause mortality and a U-shaped relationship between CaP and all-cause mortality in elderly TR patients.
doi.org/10.1097/CM9.0000000000002916
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