Introduction
Heart failure (HF) is the most prevalent reason for morbidity and mortality worldwide. Management of HF consists of pharmacotherapy and device-based therapy (1). Cardiac resynchronization therapy (CRT) has been developed as a potent treatment for advanced HF patients with prolonged QRS duration greater than or equal to 130 ms despite optimal pharmacotherapy (2). CRT improves mechanical synchrony by pacing both the LV free wall and septal. The CRT improves left ventricular (LV) ejection fraction (LVEF), survival, 6-min-walk distance, and QRS duration (3). Due to the progressive increase in the incidence of HF population and broadened indications for CRT, it is being performed more frequently worldwide (4).
A detailed coronary sinus (CS) anatomy evaluation via coronary venous angiography, which is the gold standard, is essential to ensure optimal placement of the LV lead (5). Nevertheless, this procedure necessitates contrast material administration to identify and cannulate the CS. The most common reason for failure in CRT devices is the failure to cannulate CS ostium (6). However, the contrast administration in this set of patient populations brings the risk of contrast-induced nephropathy (CIN). Major risk factors for the progression of CIN involve congestive HF, pre-existing reduced kidney function, older age, diabetes mellitus (DM), and contrast material load (7-9). CIN has been revealed to be more common than the most recognized complications of CRT implantation (10).
Besides, the development of CIN following CRT has an important negative impact on morbidity and long-term prognosis (11). Therefore, it is essential to determine risk factors for CIN to take preventive precautions. Mehran et al. (12) developed a risk score in 2004 to predict the risk of CIN after percutaneous coronary interventions (PCI). The Mehran risk score (MS) is the most widely accepted and simple to calculate tool for estimating CIN. Several risk factors have been described for CIN MS based on hypotension, use of an intra-aortic balloon, congestive HF, advanced age, anemia, DM, contrast material volume, and glomerular filtration rate (GFR). It is categorized into 4 groups according to the scores obtained from these parameters. This single-center study aimed to assess the prediction of MS on the CIN of chronic HF patients with CRT.
Methods
This single-center, retrospective study included medically refractory HF patients who underwent CRT implantation between February 2019 and February 2021. The inclusion criteria were New York Heart Association (NYHA) class II-IV disease, wide QRS in electrocardiogram (ECG) (>130 ms), and diminished LVEF (<35%) (13). Patients with active bleeding, acute renal failure before CRT procedure, liver cirrhosis, autoimmune disease, chronic or acute inflammatory diseases, end-stage malignancy, and receiving dialysis were excluded. Additionally, subjects on angiotensin receptor-neprilysin inhibitor (ARNI), renin-angiotensin-aldosterone system blockers, mineralocorticoid receptor antagonists (MRA), diuretics, and digoxin 24-48 hours before the procedure were excluded from the study.
The successful CRT implantation was defined as implantation of LV lead into the appropriate branch of the CS, a right ventricular lead in the optimal position, and a right atrial lead if needed.
Clinical assessment included the evaluation of the NYHA functional class. All patients’ 2-dimensional and Doppler echocardiographic examinations were recorded to calculate EF in terms of suitability for CRT. A 2-4 MHz transducer (Philips Affiniti 50, Philips Healthcare, Andover, Netherlands) is used for echocardiographic examinations in our clinic (14). White blood cell count, platelet count, creatinine, and hemoglobin level were obtained from the patient records.
CIN was defined as an increase in creatinine concentration 0.5 mg/dL (44 mol/L), or 25% above baseline, within 48 h of contrast administration (12). Patients were divided into two groups according to the development of CIN.
MS was calculated for all patients, which Mehran et al. (12) defined. It is calculated by summing the scores from the following findings: hypotension (5 points, if systolic blood pressure <80 mmHg for at least 1 hour requiring inotropic support), use of intra-aortic balloon pump (5 points), congestive HF (5 points, if class III/IV by NYHA classification or history of pulmonary edema), age (4 points, if >75 years), anemia (3 points, if hematocrit <39% for men and <36% for women), DM (3 points), contrast media volume (1 point per 100 mL), and estimated GFR (GFR; in mL/min per 1.73 m2; 2 points, if GFR 60 to 40; 4 points, if GFR 40 to 20; 6 points, if GFR <20). It is categorized into 4 groups: low risk, <6 points; moderate risk, 6-10 points; high risk, 11-15 points; and very high risk, >15 points). Contrast material volume was estimated using the amount for visualization of the CS.
The study was approved by the Ankara City Hospital Institutional Ethics Committee (decision no: E2-20-57, date: 16.12.2020).
Statistical Analysis
IBM Statistical Package for the Social Sciences Statistics for Macintosh, version 24.0 (IBM Corp., Armonk, New York, USA) was used to perform the statistical calculations. The results were displayed as mean±standard deviation (SD), median (interquartile range), and number (percentage), where appropriate. Kolmogorov-Smirnov test was used to test the normality of distribution. Student’s t-test and Mann-Whitney U were used for the comparison of continuous variables according to the normality. The chi-square test was used to compare the categorical variables. Logistic regression analysis was performed to explore the variables that were independently associated with a CIN diagnosis. Potential confounding factors for developing CIN were tested in univariate analysis, including age, gender, DM, hypertension, coronary artery disease, dyslipidemia, ischemic HF, treatment with an MRA, or renin-angiotensin-aldosterone system blocker, contrast material volume, baseline creatinine level, LVEF, and MS. The variables that showed a crude association with a p<0.100 in univariate analysis were entered in the multivariate model. The goodness-of-fit assumption was examined by the Hosmer-Lemeshow method and satisfied when the p-value was above 0.05. Receiver operating characteristic (ROC) curve analyses were performed to define the cut-off values for the sensitivity and specificity of MS and contrast material volume to predict the diagnosis of CIN. The area under the ROC curve (AUC) was assessed with a 95% confidence interval (CI) in addition to specificity and sensitivity. A two-sided p-value of less than 0.05 was defined to be statistically significant.
Results
Basic characteristics
The study included 144 patients (age, mean±SD: 63±10, male sex: 75%). Table 1 shows the demographic, clinical, laboratory, and treatment characteristics of the study population. Compared with CIN (-) patients, CIN (+) patients were significantly older, had higher mean creatinine levels, and lower lymphocyte count and platelet count (p=0.010, p=0.019, p=0.007, and p=0.031, respectively). There was no statistically significant difference in the frequency of smoking, DM, hypertension, dyslipidemia, chronic obstructive pulmonary disease, anemia, coronary artery disease, cerebrovascular disease, ischemic HF, peripheral artery disease, treatments, and other laboratory variables in patients with and without CIN.
In the whole group, ECG revealed a left bundle branch block in one hundred thirty-nine patients (Table 2). The remaining had the right bundle branch block. Patients with CIN had a longer length of hospital stay and received higher contrast material volume (p=0.001, and p<0.001, respectively). Patients with CIN had lower EF than CIN (-) patients (22±6% vs. 26±7%, p=0.005), and higher NYHA class III-IV (38% vs. 18%, p=0.023) (Table 2).
Mehran score evaluation
As demonstrated in Table 3, univariate logistic regression analyses showed that age [Odds ratio (OR): 1.06, 95% CI: 1.01-1.11, p=0.021], contrast volume (OR: 1.03, 95% CI: 1.02-1.05, p<0.001), creatinine level (OR: 2.85, 95% CI: 1.12-7.22, p=0.027), LVEF (OR: 0.92, 95% CI: 0.86-0.98, p=0.008), and MS (OR: 1.35, 95% CI: 1.17-1.56, p<0.001) showed association with the development of CIN. Multivariable logistic regression analyses showed contrast volume (OR: 1.02, 95% CI: 1.00-1.04, p=0.029) and MS (OR: 1.34, 95% CI: 1.10-1.63, p=0.004) independently associated with the development of CIN.
Sensitivity and specificity analysis
On admission, MS of 8.5 showed a sensitivity of 69% and specificity of 71% (AUC: 0.743, 95% CI: 0.645-0.841, p<0.001) for the prediction of CIN in this study population (Table 4). The cut-off for the contrast material volume for predicting CIN was 43 mL, with a sensitivity of 65% and specificity of 80% (AUC: 0.819, 95% CI: 0.751-0.886, p<0.001) (Figure 1, Table 4).
Discussion
This study showed that MS can be used as a predictor of CIN in patients undergoing CRT implantation, with a cut-off value of 8.5 and more than 65% sensitivity and specificity. This is the first study demonstrating that MS is an independent CIN predictor among patients undergoing CRT implantation.
CRT implantation complicated with CIN has higher mortality and morbidity than those without CIN (11). Therefore, determining the factors that may cause CIN in the preoperative period will help identify the patients in the risky group.
CIN is one of the most important complications of percutaneous cardiovascular procedures with an important effect on the long-term prognosis in this set of patients (11,15,16). Several potential pathophysiological pathways that can cause CIN have been reported. However, the pathogenesis of kidney damage is still not precisely elucidated. Nonetheless, iodinated contrast causes direct cellular damage to renal tubular cells leading to swelling, blebbing, and apoptosis in tubular cells (17). Additionally, microembolism due to catheter manipulation, which is not easily identifiable clinically may, at least in part, lead to CIN (18).
Although PCI and coronary angiography are the most common causes for developing CIN, the incidence of CIN after CRT implantation is similar to that of coronary procedures. CIN is a serious and frequent procedural complication of CRT implantation with a significant negative influence on long-term survival. Generally, less contrast volume is used in CRT implantation than PCI. Besides, patients with chronic HF have more comorbid chronic kidney disease. Therefore, although less contrast is required in the CRT procedure, the risk of developing CIN is increased (11).
CIN incidence was 20.1% in our study. This number is higher than the findings published by other authors despite the use of less amount of contrast medium (10,11,19). Our study sample received a mean contrast volume of 36 mL. In other studies, however, more than 100 mL contrast volume was used (10,11,19). Nonetheless, our study repeatedly confirmed that CIN is the most common procedural complication in patients undergoing CRT implantation. Less contrast usage was not associated with failed LV lead implantation. The decrease in failed LV lead implantation is associated with increased operator experience (19). Thus, CRT implantation by experienced operators is an essential preventive strategy in patients with high-risk factors.
HF and lower EF are among the most significant risk factors for CIN development in patients receiving CRT implantation (10,12). In our study, patients with CIN had lower EF compared to patients without CIN. However, lower EF was not found as an independent risk factor for the development of CIN. This finding may be related to the small number of patients in the study. CIN also negatively influences the recovery of EF and survival in patients undergoing CRT implantation (20). Cardiorenal syndrome (CRS) type 3 is a subtype of the CRS. This type of CRS leads to acute kidney injury that aggravates and contributes to acute cardiac injury (21). This association can be explained by the close relationship between renal and cardiac function. As the reduction in cardiac output damages kidney functions, impaired kidney functions may also cause worsening in cardiac performance. Survival benefit in CRT responders is reduced if CIN occurs after the procedure (20).
MS has been developed to detect patients at risk of CIN in patients undergoing PCI. Although persistent renal dysfunction requiring routine hemodialysis after CIN is extremely rare, up to 45.9% of patients with CIN may have permanent renal failure (22). This complication is also associated with higher mortality and morbidity (11).
There are some limitations of this study. Firstly, this is a single-center study with relatively small sample size. Second, it is a retrospective study, and the results need to be further verified by prospective studies. Finally, the results are cross-sectional, precluding the establishment of a causal relationship.
Conclusion
We found a higher MS as an independent risk factor for developing CIN in HF patients undergoing CRT implementation. A score of MS above 8.5 may warn the operators to take stricter preprocedural precautions and modify the potential risk factors for CIN after CRT implantation. Therefore, the data obtained from this study suggest that MS can be used in risk stratification for CIN following CRT implementation in individuals with advanced HF.
Ethics
Ethics Committee Approval: The study was approved by the Ankara City Hospital Institutional Ethics Committee (decision no: E2-20-57, date: 16.12.2020).
Informed Consent: Retrospective study.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Concept: A.E., M.Ö., A.A., Design: M.A.E., M.Ö., M.K., Data Collection or Processing: M.E., K.D., A.A., Analysis or Interpretation: A.E., A.B.A., S.T., Literature Search: A.C.Ö., M.E., K.D., Ç.Y., Writing: M.A.E., M.K., A.B.A.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
