To the Editor: Tricuspid regurgitation (TR) associated with valve disease is a general medical issue with growing prevalence and socioeconomic burden. TR, especially moderate or severe TR, has been reported to be associated with an increased risk of heart failure and mortality.[1] Studies have shown that blood calcium levels and blood phosphorus levels have a great influence on the human body, especially on the cardiovascular system. Elevated serum calcium levels were reported to be a risk factor for cardiovascular disease.[2] A meta-analysis reported that moderate dietary calcium intake protects against cardiovascular and all-cause mortality and that calcium supplementation reduces mortality in women.[3]

To provide a better treatment, it is important to understand the relationship between calcium, phosphorus, and all-cause mortality in TR patients. At present, the relevant evidence is not sufficient. 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 the present study were selected from the China Elderly Degenerative Valve Disease (China-DVD) study (https://clinicaltrials.gov/, No. NCT02865798). China-DVD is 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 throughout China. The China-DVD study was conducted according to the Declaration of Helsinki. The Institutional Review Board at each center approved the study protocol. Written informed consent was obtained from all participants. In China-DVD, 8929 consecutive patients with moderate or severe native VHD, which was defined by echocardiography using an integrative approach according to the 2014 American College of Cardiology/American Heart Association guidelines, were included. Patients were followed for 1 year. Patients in the present study were selected based on the following considerations: (1) disease type: TR; (2) echocardiography measurement at baseline; and (3) complete measurements of serum calcium, serum phosphorus, and albumin at baseline. Patients were excluded based on the following considerations: (1) infective endocarditis;(2) history of prior valve intervention; (3) other types of VHD; and (4) outliers (a value greater than the mean plus three times standardized deviation [SD] or less than the mean minus three times SD, e.g., mean serum calcium concentration is 2.2 ± 0.3 mmol/L, a measurement of 0.8 is an outlier).

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 then measurements of calcium, phosphorus, and albumin were performed using a biomedical analyzer (LaboSpect 008AS, FUJIFILM, Tokyo, Japan).

The endpoint of the present 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 shown in Supplementary Material, https://links.lww.com/CM9/B787. The formulas for the CorCa calculation and albumin calculation are shown below.

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 were 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 inflection points were 3.4 mg/dL and 3.6 mg/dL according to the estimated hazard ratio (HR) by the RCS model. We then divided patients into three subgroups according to inflection 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 [Figure 1A]. Adjusted confounding factors in the above full Cox model were also considered [Figure 1B], 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.

Figure 1:

Survival analysis of phosphorus and CaPs among elderly TR patients. (A) Survival plot by different phosphorus level, confounders not adjusted; (B) Survival plot by different phosphorus level, with confounders adjusted; (C) Survival plot by different calcium-phosphorus product level, confounders not adjusted; (D) Survival plot by different calcium-phosphorus product level, with confounders adjusted. CaPs: Calcium-phosphorus products; TR: Tricuspid regurgitation.

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 inflection 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 inflection 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 [Figure 1C]. 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 [Figure 1D]. 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.[4] Chen et al[4] 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[5] 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.

Funding

This study was supported by grants from the National Key Research and Development Program of China (No. 2020YFC2008100), the National Science and Technology Support Project of China (No. 2015BAI12B02), and the Chinese Academy of Medical Sciences Fuwai Hospital high-level hospital clinical research project (No. ZBA2023-GSP-GG-38).

Conflicts of interest

None.

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