DOI: https://doi.org/10.21203/rs.3.rs-2206509/v1
Background: Cardiac valve calcification predisposes patients to a higher risk of adverse events. This study aimed to investigate the association between cardiac valve calcification and 1-year mortality in diabetic patients after lower-extremity amputation.
Methods: Diabetic patients requiring lower-extremity amputation were retrospectively studied. Preoperative detailed anamnesis was taken. Cardiac valve calcification was assessed using echocardiography at baseline. One-year follow-up was conducted and included clinical visits, hospital record assessment, and telephone reviews to obtain the survival status of patients.
Results: Ninety-three diabetic patients participated in the study. The 1-year follow-up mortality rate after amputation was 24.7%. Compared to the survival group, the prevalence of cardiac valve calcification and RCRI were higher in the mortality group. In the Cox regression analysis, cardiac valvular calcification (HR=3.427, 95% CI=1.125-10.443, P=0.030) was found to be an independent predictor of all-cause mortality after amputation. In addition, the patients with both aortic valve calcification and mitral annular calcification had a higher all-cause mortality rate (50%). Receiver operator characteristic curve analysis showed a stronger predictive ability when using a combination of calcified valve number and RCRI (AUC=0.786 95%, CI=0.676-0.896, P=0.000).
Conclusion: In diabetic patients after lower-extremity amputation, cardiac valve calcification was associated with all-cause mortality during 1-year follow-up. Combination of calcified valves number and RCRI showed a stronger predictive valuefor mortality.
Diabetic foot is a complication resulted from long-term poor control of diabetes, which seriously reduces the quality of life. Persistent damage or inadequate healing of the diabetic foot ulcer may result in limited mobility, frequent hospitalization, and eventually lead to lower extremity amputation. Several studies have shown the high mortality of patients after lower extremity amputation.[1, 2] The 5-year mortality rate after amputation is estimated at 39–68%.[3] Hence, it is important to identify the risk factors for mortality following amputation, which may influence our perioperative strategy. The Revised Cardiac Risk Index (RCRI) is widely used to identify patients with perioperative cardiovascular risk. It consists of 6 parts: coronary artery disease, cerebrovascular disease, heat failure, insulin-requiring diabetes, renal insufficiency and high-risk noncardiac surgery.[4] There are many risk factors affecting the survival rate after surgery, and the RCRI does not include those subclinical factors. Thus, this risk stratification method has its own limitation.
Cardiac valvular calcification, which are common echocardiographic findings in elderly, was found to have associations with the component of RCRI in several research.[5, 6] Some studies reported that more than half of patients with end-stage kidney disease have cardiac valvular calcification.[7] A recently research showed that diabetic patients have an increased risk of aortic stenosis.[8] Moreover, previous clinical studies have found that calcification of the heart valve is associated with a high prevalence of risk factors that can promote atherosclerosis.[9–11] Valvular calcification has been shown to be associated with an increased risk of coronary events, cardiovascular mortality, and all-cause mortality.[12–16] To date, no study has evaluated the association of calcified heart valve and mortality in diabetic patients who underwent lower extremity amputation. This study aimed to investigate the association of cardiac valvular calcification with 1-year mortality after lower extremity amputation.
This was a single-center retrospective study based on patients of the Sun Yat-sen Memorial Hospital, and the study was approved by the medical ethics committee of the Sun Yat-sen Memorial Hospital. We recruited consecutive patients who were admitted to the Sun Yat-sen Memorial Hospital for diabetic foot ulcers that needed amputation surgery between July 2017 and March 2021 and were followed up for 1 year after amputation surgery. Inclusion criteria included the following: (1) age ≥ 18 years old; (2) underwent echocardiography; and (3) with diabetic foot ulcers that needed lower extremity amputation after orthopedist’s assessment. Patients were excluded if they met the following criteria: (1) fractures due to traumatic reasons that required extremity amputation; (2) amputation level below the ankle; (3) incomplete patient information; (4) severe sepsis that required vasoactive agent treatment; (5) rheumatic heart disease, infective endocarditis or malignant tumor; or (6) heart valve surgery. An orthopedist and a consultant diabetologist assessed all the patients. Clinicians evaluated the severity of the infection based on IWGDF/IDSA classification and the severity of the ischemia based on vascular imaging.
Clinical characteristics of each patient, including baseline demographic data, prior medical history (such as coronary artery disease, diabetes mellitus, hypertension, stroke history, heart failure history), smoking history and body mass index (BMI), were collected on admission. BMI was calculated as weight (kg)/height (m)2. The Revised Cardiac Risk Index (RCRI) consists of 6 parts, each worth one point (heart failure history, cerebrovascular disease, ischemic heart disease, creatinine > 177 µmol/L, insulin-requiring diabetes, and high-risk noncardiac surgery). Patients were required to take the laboratory examination as the baseline information before surgery, including blood routine, blood biochemistry, glycosylated hemoglobin, NT-pro BNP, serum creatinine, and blood lipids. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
All echocardiographic examinations were performed using an ultrasound system (Vivid 7; GE Health Medical, Milwaukee, WI, USA) equipped with a multifrequency transducer (M3S 1.7/3.4MHZ). The echocardiologists who performed the echocardiographic evaluation were blinded to the clinical materials before the amputation surgery. Echocardiographic measurements of all chambers were taken according to the current recommendations. Left ventricular ejection fraction (LVEF) was calculated by using the modified Simpson’s method. Mitral annular calcification was defined by increased echodensity located at the junction of the atrioventricular groove and posterior mitral leaflet on the parasternal long-axis, short-axis, or apical four-chamber view. Aortic valve calcification was defined as focal areas of increased echogenicity and thickening of the aortic leaflets.
This study obtained the survival status of patients within one year through follow-up in the outpatient department. If the patient did not undergo routine outpatient follow-up within one year after surgery, telephone follow-up was conducted. Death confirmation was achieved by follow-up in the outpatient department, as well as telephone follow-up. The content of the follow-up included information on survival status, postoperative recovery, related complications and other information. Based on this, we discovered through statistical analysis that risk factors can change the mortality rate.
All statistical analyses were performed with SPSS 22.0 software. Nonnormally distributed variables are represented as the median (minimum-maximum) and were compared with the Mann–Whitney U test. Normally distributed continuous variables are represented as the mean ± standard deviation values and were compared with Student’s t test. Categorical variables were represented with absolute (%) and were compared using the chi-square test and Fisher’s exact test. The Kaplan–Meier method and the log-rank test were used to analyze survival probabilities in the studied patients. Cox regression analysis was constructed to study associations between heart valve calcification, conventional risk factors and all-cause mortality after amputation. In Cox regression models, the time at risk was from the time of enrollment until death or until the end of the study. An ROC curve was calculated to evaluate the unity of calcified cardiac valve in predicting 1-year mortality in the study patients. A two-sided p < 0.05 was considered statistically significant.
Ninety-three patients constituted the final study population. The prevalence rates of coronary artery disease, heart failure history, cerebrovascular disease history, and hypertension were 24.7%, 52.7%, 20.4%, and 68.8%, respectively. Twenty-three (24.7%) patients died during the follow-up.
Patients who died during the follow-up had a longer duration of diabetes (Table 1). The prevalence of preexisting heart failure was higher among patients in the mortality group than among those who survived (78. 3% vs. 44.3%, P = 0.005). The percentage of patients with a preexisting coronary artery disease history and stroke history showed no significant difference between the 2 groups. The revised cardiac risk index of the mortality group was higher than that of the survivor group (3 vs. 2, P = 0.001). In addition, 17 (73.9%) patients in the mortality group had cardiac valve calcification, which was significantly higher than the proportion of cardiac valvular calcification in the survivor group (47.1%, P = 0.025). The prevalence of calcified aortic valve was significantly higher in the mortality group (70.0% vs. 42.8% P = 0.026). Although the mortality group had a higher proportion of mitral valve calcification (21.7% vs. 10%), there was no significant difference between the two groups (P = 0.145). In comparison to the patients who died during the follow-up, the ejection fraction was significantly higher in patients who survived (P = 0.047). Patients in the mortality group had lower HDL-c, higher procalcitonin (PCT), higher urea nitrogen, and higher NT-proBNP at admission than those who survived.
| Variable | Survivor (n = 70) | Mortality (n = 23) | P |
|---|---|---|---|
| Gender, n (%) Male Female | 41 (58.6) 29 (41.4) | 16 (69.6) 7 (30.4) | 0.461 |
| Age (year) | 68.09 ± 10.69 | 66.39 ± 9.60 | 0.501 |
| BMI (kg/m2) | 21.62 (18.82–23.75) | 22.86 (21.19–23.44) | 0.160 |
| History of smoking, n (%) | 26 (37.1) | 10 (43.5) | 0.588 |
| Hypertension, n (%) | 48 (68.6) | 16 (69.6) | 0.929 |
| History of coronary artery disease, n (%) | 15 (21.4) | 7 (30.4) | 0.378 |
| History of cerebrovascular disease, n (%) | 12 (17.1) | 7 (30.4) | 0.138 |
| History of chronic heart failure, n (%) | 31 | 18 | 0.005 |
| Revised Cardiac Risk Index | 2 (1–2) | 3 (2–4) | 0.001 |
| Duration of diabetic history (year) | 10 (5–15) | 20 (7–20) | 0.013 |
| eGFR (ml/min∙1.73m2) | 59.75 ± 29.73 | 48.87 ± 26.65 | 0.133 |
| HbA1c (%) | 9.24 ± 3.95 | 9.28 ± 2.55 | 0.968 |
| Serum Creatinine (µmol/L) | 95 (68–132) | 103 (77–283) | 0.262 |
| BUN (mmol/L) | 9.23 ± 8.29 | 13.53 ± 9.55 | 0.041 |
| LDL-c (mmol/L) | 2.32 ± 0.89 | 2.13 ± 0.63 | 0.364 |
| HDL-c (mmol/L) | 0.81 ± 0.28 | 0.58 ± 0.15 | 0.001 |
| TG (mmol/L) | 1.32 ± 0.89 | 1.22 ± 0.45 | 0.622 |
| Cholesterol (mmol/L) | 3.49 (2.67–4.27) | 3.07 (2.37–3.60) | 0.072 |
| Serum Uric Acid (µmol/L) | 330.26 ± 138.40 | 381.12 ± 150.73 | 0.231 |
| PCT (ng/ml) | 0.13 (0.60–0.77) | 0.39 (0.21–1.23) | 0.022 |
| WBC (×109/L) | 14.23 ± 7.29 | 18.29 ± 9.65 | 0.074 |
| NT-proBNP (pg/ml) | 2118 (483–4702) | 9917 (3254–25621) | 0.000 |
| Cardiac valvular calcification, n (%) | 33 (47.1) | 17(73.9) | 0.025 |
| Eject fraction (%) | 64 (59–71) | 61.50 (50.50–66) | 0.047 |
| Aortic valve calcification, n (%) | 30 (42.9) | 16 (26.1) | 0.026 |
| Mitral annular calcification, n (%) | 7 (10%) | 5 (21.7) | 0.145 |
| A 2-tailed p value < 0.05 was considered statistically significant. BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated hemoglobin, type A1C; BUN, blood urea nitrogen; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol; TG, triglyceride; PCT, procalcitonin; WBC, white blood cell; NT-proBNP, N-terminal pro-B-type natriuretic peptide. | |||
To identify independent predictors of mortality, variables that had p < 0.1 in univariate analysis (heart failure history, RCRI, duration of diabetes, BUN, serum creatinine, HDL-c, cholesterol, WBC, NT-proBNP, eject fraction, cardiac valvular calcification) were analyzed using backward multivariate analysis (Table 2). The duration of diabetes (HR = 1.067, 95% CI = 1.008–1.128), HDL-c (HR = 0.020, 95% CI = 0.001–0.338), NT-pro BNP (HR = 1.000, 95% CI = 1.0–1.0), and cardiac valvular calcification (HR = 3.427, 95% CI = 1.125–10.443) were independent predictors for all-cause mortality during the 1-year follow-up. Moreover, after adjusting for the same variables (Hdl-c, NT-pro BNP, duration of diabetes), aortic valve calcification was found to be an independent predictor for mortality (HR = 2.882 95% CI = 1.012–8.209), while the prediction value of mitral valve calcification showed no statistical significance (Table 3).
| Variable | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | |
| Age | 0.989 | 0.952–1.027 | 0.563 | |||
| BMI | 1.065 | 0.953–1.190 | 0.269 | |||
| Gender | 1.250 | 0.530–2.948 | 0.610 | |||
| Hypertension | 1.023 | 0.421–2.488 | 0.960 | |||
| History of smoking | 1.248 | 0.547–2.845 | 0.599 | |||
| History of CAD | 1.483 | 0.610–3.605 | 0.385 | |||
| History of cerebrovascular disease | 1.974 | 0.804–4.845 | 0.138 | |||
| History of heart failure | 3.845 | 1.426–10.368 | 0.008 | |||
| Revised Cardiac Risk Index | 1.861 | 1.312–2.639 | 0.000 | |||
| Duration of diabetes | 1.076 | 1.022–1.132 | 0.005 | 1.067 | 1.008–1.128 | 0.024 |
| eGFR | 0.989 | 0.974–1.004 | 0.146 | |||
| HbA1c | 0.998 | 0.879–1.133 | 0.973 | |||
| BUN | 1.032 | 1.000-1.064 | 0.047 | |||
| Serum creatinine | 1.002 | 1.000-1.003 | 0.017 | |||
| LDL-c | 0.775 | 0.438–1.371 | 0.382 | |||
| HDL-c | 0.019 | 0.002–0.176 | 0.001 | 0.020 | 0.001–0.338 | 0.007 |
| TG | 0.844 | 0.441–1.617 | 0.610 | |||
| WBC | 1.049 | 1.004–1.096 | 0.034 | |||
| PCT | 0.917 | 0.731–1.150 | 0.451 | |||
| NT-proBNP | 1.000 | 1.000–1.000 | 0.000 | 1.000 | 1.000–1.000 | 0.001 |
| Eject fraction | 0.942 | 0.898–0.988 | 0.014 | |||
| Cardiac valve calcification | 2.725 | 1.074–6.913 | 0.035 | 3.427 | 1.125–10.443 | 0.030 |
| A 2-tailed p value < 0.05 was considered statistically significant. | ||||||
| BMI, body mass index; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated hemoglobin, type A1C; BUN, blood urea nitrogen; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol; TG, triglyceride; WBC, white blood cell; PCT, procalcitonin; NT-proBNP, N-terminal pro-B-type natriuretic peptide. | ||||||
| Univariate | Adjusted | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | |
| Mitral Annular Calcification | 2.066 | 0.767–5.566 | 0.151 | 3.053 | 0.939–9.927 | 0.064 |
| Aortic Valve Calcification | 2.596 | 1.068–6.312 | 0.035 | 2.882 | 1.012–8.209 | 0.048 |
| The adjusted model factors including NT-proBNP, HDL-c, and duration of diabetes. | ||||||
Kaplan–Meier graphs showed that mortality differed from the first day following the index event for patients with cardiac valvular calcification and without calcification (Fig. 1, P = 0.025).
To further evaluate the influence of cardiac valvular calcification on 1-year mortality, patients were divided into three groups on the basis of calcified valve number (Fig. 2). The patients with both calcified aortic valve and calcified mitral valve had a higher all-cause death rate (50%). The mortality rate of patients who had calcified aortic valves or calcified mitral valves was higher than that of patients without valve calcification (31.0% vs. 14.0%).
Receiver operator characteristic curve analysis showed a strong predictive ability of calcified valve number for mortality after 1-year follow-up (Fig. 3, AUC = 0.654, 95% CI = 0.524–0.783 P = 0.028). The area under the ROC curve for RCRI to predict 1-year mortality was 0.724 (95% CI = 0.604–0.843, P = 0.001). A stronger performance of the combination with calcified valve number and RCRI was noted when ROC analysis was conducted (AUC = 0.786, 95% CI = 0.676–0.896 P = 0.000).
This study found that the presence of cardiac valve calcification was strongly associated with an increased risk of mortality in diabetic patients who underwent lower-extremity amputation after 1 year of follow-up.
The precise biological mechanisms that explain the association of cardiac valve calcification with an increased risk of all-cause mortality have not been well defined to date. Atherosclerosis may be the point linking valve calcification with an increased risk of postoperative mortality in diabetic patients after amputation surgery. The hyperglycemia environment which resulted from the poorly controlled diabetes, can both trigger faster valve calcification progression and impact atherosclerosis progression.[17–21] A plausible explanation for our finding is that heart valve calcification is a manifestation of widespread atherosclerosis. Previous clinical studies have shown that valve calcification shares multiple risk factors with atherosclerosis (e.g., advanced age, diabetes mellitus, smoking, BMI, hypertension).[9, 10] These risk factors are widespread in the majority of diabetic patients with diabetic foot syndrome. There are findings with respect to the association between calcified mitral valve and risk of atrial fibrillation, stroke, cardiovascular disease, and cardiovascular mortality.[13, 22–24] The presence of a calcified aortic valve was also associated with an increased risk of cardiovascular death and myocardial infarction.[25–28] Moreover, a calcified mitral valve is found to be an independent predictor of the presence of severe coronary stenosis[29]. As observed in several studies, patients with several forms of atherosclerotic vascular disease (e.g., carotid artery, coronary artery) have a high prevalence of heart valve calcification.[30–32] Therefore, it is more likely to consider heart valve calcification as a marker for atherosclerosis disease burden. The calcification of the heart valve can be the common endpoint pathophysiological process that affects the vascular system.
Predictors that help to improve the specificity of cardiovascular disease risk stratification are necessary for patients who will undergo amputation during the preoperative assessment. Guidelines recommend the use of the Revised Cardiac Risk Index (RCRI) for perioperative risk assessment for noncardiac surgery. In our study, the number of calcified valves was found to be a strong predictor of 1-year mortality. After a combination of the calcified valve number and the classical index RCRI, a stronger predictive ability was shown. Possible explanation for the combination of calcified valve number and RCRI being better predictors are as follows: The existence of heart valve calcification may reflect the severity of the subclinical vascular damage caused by the risk factors, while the RCRI index is mainly calculated with clinical organ dysfunction. Patients with diabetic foot syndrome often have different forms of artery diseases, which are often asymptomatic or subclinical, such as coronary artery disease. Coronary artery disease has become one of the main causes of death among diabetic patients.[33] However, before the onset of myocardial infarction or sudden cardiac death, coronary artery disease in these patients is often asymptomatic.[34] The study found that 30.5% of patients with diabetes had significant coronary artery disease despite the absence of symptoms. Moreover, with the limited joint mobility and chronic pain of diabetic foot ulcers, patients show decreased exercise capacity, which can make stable coronary artery disease subclinical. Previous clinical research has shown associations between calcified aortic valves and markers of subclinical atherosclerosis (carotid artery intima-media thickness, carotid plaques, aortic pulse wave velocity).[35] These findings support that the combination of calcified cardiac valve number and RCRI improves the risk stratification in patients who underwent amputation.
Our study has several limitations. First, this study was a single-center study and had a limited sample size. Only 93 patients that need lower-extremity amputation in Sun Yat-sen Memorial Hospital were enrolled in this study. Therefore, further research based on multiple centers and larger sample size is needed. Second, the patients enrolled in this study didn’t take coronary angiography or brain CT, which could provide more information about the artery to help analyze mechanisms. Thus, further research with more imaging data is still needed.
In the present study, cardiac valve calcification was a strong predictor of all-cause mortality in patients with diabetes who underwent lower extremity amputation. Combining the number of calcified cardiac valves and the RCRI in a prognostic model could provide extra improvement in the clinical risk stratification of diabetic patients who underwent amputation. Echocardiographic evaluation of heart valve calcification provides an alternative assessment of atherosclerosis burden, which is simple and widely available. Thus, the detection of valve calcification may have additional benefits in the identification of high-risk patients. Such an approach should result in an earlier and proper treatment strategy in these vulnerable patients due to the improvement of cardiovascular risk stratification and preoperative evaluation.
BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated hemoglobin, type A1C; BUN, blood urea nitrogen; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol; TG, triglyceride; PCT, procalcitonin; WBC, white blood cell; NT-proBNP, N-terminal pro-B-type natriuretic peptide; RCRI, Revised cardiac risk index.
8.1 Ethics approval and consent to participate
This retrospective research was approved by the Research Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University. [ SYSKY-2022-035-01]. Each participant provides written informed consent to collect all data before the study and was anonymized before analysed. This study was conducted with observance of the Declaration of Helsinki and the National Ethical Guidelines in Biomedical Research in China.
8.2 Consent for publication
Not applicable
8.3 Competing interest
None.
8.4 Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
8.5 Availability of data and materials
The datasets generated and analysed during the current study are not public available due to the privacy protection and a number of researches on cardiac valve calcification may be continued, but are available from the corresponding author ([email protected]). The processed data required to reproduce these finding cannot be shared at this time as the data also form part of an ongoing study.
8.6 Author’s contributions
YWB analyzed and interpreted the patient data regarding the heart valve calcification and the mortality after amputation. ZJF and LL were the major contributor in writing the manuscript. All authors read and approved the final manuscript.
8.7 Acknowledgements
The authors thank all participants for their contribution to the study, without which this research would not be possible.