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9th January 2023
Combining a patient’s coronary artery calcium score and their cystatin C level provides an incremental risk assessment of major adverse cardiac and cerebrovascular events (MACCEs) and all-cause death, in patients symptomatic with chest pain according to the findings of a study by Chinese researchers.
The World Health Organisation describes how cardiovascular diseases are the leading cause of global deaths, with an estimated 17.9 million lives lost each year. Consequently, risk stratification tools are required to inform on the subsequent management decisions for patients. One such measure to assist in cardiovascular disease risk stratification is the coronary artery calcium (CAC) score, which is a highly specific feature of coronary atherosclerosis. In fact, the extent of CAC has been shown to accurately predicts 15-year mortality in a large cohort of asymptomatic patients. Another potentially useful marker is Cystatin C (Cys-C) which is cysteine protease inhibitor produced at a constant rate by all nucleated cells and used as a sensitive marker of renal function. Moreover, Cys-C has been found to be a strong predictor of the risk of death and cardiovascular events in elderly patients.
Given the potential and independent value of these markers for predicting the risk of a cardiovascular event, the Chinese researchers wondered if there was an association between baseline CAC scores and Cys-C levels and both MACCEs and all-cause death in symptomatic, chest pain patients. They included all individuals presenting with symptomatic chest pain suggestive of CHD and who were referred for cardiac computed tomography (CT) by their cardiologists, which enabled assessment of the coronary artery calcium score. Based on the CT findings, patients were classified into two groups: those with CAC scores < 100 or CAC scores ≥ 100. Blood samples were taken to measure Cys-C levels and risk stratification of CAC score and Cys-C level were as follows: low risk (CAC score < 100 or Cys-C < 0.995 mg/L. and high risk (CAC score ≥ 100 or Cys-C ≥ 0.995 mg/L).
Coronary artery calcium and cysteine C levels and MACCEs
A total of 7140 participants with a median age of 63 years (64.9% male) were included and followed for a median of 1,106 days. During the period of follow-up, 305 MACCEs and 191 all-cause death events were observed.
A higher incidence of MACCEs were independently associated with CAC scores ≥ 100 (hazard ratio, HR = 1.46, 95% CI 1.15 – 1.85, p = 0.002) and where Cys-C levels were ≥ 0.995 mg/L (HR = 1.57, 95% CI 1.24 – 2.00, p < 0.001).
When categorised as high risk (i.e., CAC score ≥ 100 or Cys-C ≥ 0.995 mg/L), patients also had a significantly increased risk of MACCEs (HR = 2.33, 95% CI 1.64 – 3.29, p < 0.001). In addition, this high risk pattern was also associated with a significantly greater risk of all-cause mortality (HR = 2.85, 95% CI 1.79 – 4.55, p < 0.001). In fact, even in patients with CAC scores of < 100 but a Cys-C ≥ 0.995 mg/L, there was an increased risk of MACCEs (HR = 1.76, p = 0.003) and all-cause mortality (HR = 2.02, p = .007).
The authors concluded that the combined stratification of CAC score and Cys-C showed an incremental risk of MACCEs and all-cause death thus reflecting complementary prognostic value of these measures.
Luo F et al. Coronary artery calcium and cystatin C for risk stratification of MACCEs and all-cause death in symptomatic patients. Clin Cardiol 2022
17th October 2022
Cystatin C (CC) is a serine protease inhibitor that can be used as a marker of glomerular filtration rate (GFR). In fact, there is a suggestion that measurement of cystatin C should be used for the initial prediction of GFR of a patient and among critically ill patients, serum CC levels significantly outperforms serum creatinine for the detection of an impaired GFR. Moreover, other work has shown that CC-based estimates of GFR in both the elderly and ethnically diverse populations in comparison to serum creatinine, was a better predictor of all-cause mortality. While GFR derived estimates from either CC or creatinine generally agree, a decrease in the CC estimate compared to that of creatinine has been suggested to be due to what has been described as shrunken pore syndrome (SPS). It has since been recognised that SPS has been associated with a substantial increase in mortality or morbidity in all investigated populations.
However, whether cystatin C-based estimates of GFR and SPS are linked to a higher mortality among intensive care unit (ICU) patients with sepsis is uncertain and was the subject of the present study by Swedish researchers. The team undertook a post hoc analysis of data from the FINNAKI study which was a prospective observational study of acute kidney injury patients. For the present analysis, included patients were those with severe sepsis either upon ICU admission or which developed during the period of study. Plasma samples were used to measure both cystatin C and creatinine levels and from which GFR estimates were calculated. The primary outcome was 90-day mortality, whereas secondary outcomes were the development of acute kidney injury (AKI) between 12 and 5 days after ICU admission and renal replacement therapy. CC plasma levels estimated GFR based on CC and creatine were divided into quartiles.
Cystatin C measurements and mortality
A total of 802 patients with a mean age of 65 years (35.9% female) were included. The presence of SPS was present in 9.9% of patients when using an estimated GFRCystatin to GFRcreatinine cut-off ratio of 0.6 and 20% when the cut-off was set at 0.70. A total of 176 patients developed AKI between 12 hours and 5 days after ICU admission.
For plasma CC levels in the highest quartile, there was a positive and significant association with increased 90-day mortality compared to the lowest quartile (hazard ratio, HR = 4.15, 95% CI 2.17 – 7.91, p < 0.001). Similarly, there was a significant association with 90-day mortality for the lowest quartile of CC estimated GFR compared to the highest (HR = 4.45, 95% CI 2.28 – 8.68, p < 0.001). The association with SPS was also significant whether the cut-off was 0.6 or 0.70. In contrast, there was no significant association between 90-mortality and creatinine-based GFR estimates. Even after corticosteroid use in the treatment of septic shock, the associations for serum CC and estimated GFR remained significant although the association for SPS with a cut off of 0.6 was no longer significant (p = 0.14). When the researchers if the association between CC levels and 90-mortality were also linked to the development of AKI within 5 days, the analysis revealed how this association was maintained for the highest quartile of serum CC levels (HR = 4.09, 95% CI 2.14 – 7.80, p < 0.001), as well as CC estimated GFR and SPS.
The authors concluded that higher cystatin C levels together with a reduced CC-based estimate of GFR and the presence of SPS in patients with SPS in ICU was associated with a higher 90-day mortality and that a higher incidence of AKI does not explain this association.
Linne E et al. Cystatin C and derived measures of renal function as risk factors for mortality and acute kidney injury in sepsis – A post-hoc analysis of the FINNAKI cohort J Crit Care 2022