Patients and methods: The retrospective study included 240 patients (121 females, 119 males; mean age 77.5±7.6 years; range, 52 to 95 years) who underwent TAVI between January 2015 and January 2020 in two centers. Patient characteristics were compared between two groups according to mortality during follow-up (the mortality group and the survival group). The value of the UAR in predicting mortality was evaluated with receiver operating characteristic curve analysis. Predictors of mortality after TAVI were investigated with Cox regression analysis.

Results: In-hospital mortality developed in 16 (6.7%) patients, and postdischarge all-cause mortality was observed in 41 (17.1%). The two-year mortality rate was determined to be 15%. The rate of systolic heart failure, systolic pulmonary artery pressure, and UAR were found to be significantly higher in the mortality group (p=0.007, p=0.036, and p<0.001, respectively). The diagnostic power of UAR in predicting mortality was poor (the area under the curve=0.671, confidence interval [CI]: 0.589-0.753, p<0.001). Independent predictors of mortality after TAVI were UAR >2.03 (hazard ratio=2.958, CI: 1.623-5.393, p<0.001) and platelet count (hazard ratio=0.996, CI: 0.992-1.000, p=0.05).

Conclusion: Uric acid/albumin ratio was found to be an independent predictor for short-and long-term all-cause mortality in patients who underwent TAVI.

Albumin not only provides intravascular oncotic pressure and functions as a hormone, drug, and free fatty acid transporter but also plays an important role as an anti-inflammatory and antiapoptotic factor and provides protection against oxidative stress.[5-7] Serum levels of albumin may be reduced due to reduced synthesis in the liver, malnutrition, increased catabolism, reduced absorption from the gastrointestinal system, and inflammation-related capillary leakage.[8] Low levels of serum albumin are associated with coronary artery disease, acute renal failure, and all-cause mortality.[9,10]

Uric acid is the end-product of the purine metabolism. Two-thirds of uric acid is excreted by the kidneys, while the remaining one-third is excreted by intestinal uricolysis.[11,12] An increased level of uric acid is associated with endothelial dysfunction, increased inflammation and oxidative stress, and activation of the renin angiotensin aldosterone system.[13,14]

An increased level of uric acid is also an independent predictor of cardiovascular disease, aortic dilatation, hypertension, cardiovascular event, kidney failure, and all-cause mortality.[15-18]

A previous study showed that uric acid/albumin ratio (UAR) was shown to be associated with shortterm mortality in acute renal failure patients.[] Similarly, Wang et al.[20] found that UAR was an independent risk factor for postoperative long-term mortality in type A aortic dissection patients.

To the best of our knowledge, no study has been conducted to investigate whether UAR is an independent predictor for mortality following TAVI. Therefore, this study aimed to evaluate the prognostic value of UAR for mortality in TAVI patients.

The demographic, clinical, laboratory, and procedural characteristics of the patients were recorded. The laboratory results were obtained from fasting blood samples taken between 9:00 am and 12:00 am before the procedure. The follow-up periods and mortality status of the patients were obtained from the national healthcare system. All patients underwent two-dimensional echocardiography within 24 h before the procedure. Left ventricular ejection fraction was calculated using the modified Simpson method. Patients with a fasting blood glucose >126 mg/dL measured on two separate occasions during hospitalization and those receiving antidiabetic treatment were accepted as diabetic. Patients with brachial blood pressure >140/90 mmHg measured on two separate occasions during hospitalization and those receiving anti-hypertensive treatment were accepted as hypertensive. A left ventricular ejection fraction <40% was accepted as systolic heart failure. The glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula.[21]

Statistical analysis
Statistical analyses were performed using the MedCalc version 20.014 software (MedCalc Software Ltd., Ostend, Belgium). Continuous variables with normal distribution according to the Kolmogorov-Smirnov test were expressed as mean ± standard deviation, and those not showing normal distribution were presented as median (interquartile range [IQR]). Categorical variables were expressed as number (n) and percentage (%). Comparisons of the variables between the two groups were performed with the paired samples t-test, Mann-Whitney U test, and the chi-square test. The receiver operating characteristic curve analysis was used to determine the diagnostic power of UAR and albumin level and the cutoff value of UAR for the optimal sensitivity and specificity in predicting mortality. The Kaplan-Meier survival analysis and the log-rank test were used to determine and compare the survival periods of the two groups separated by the cutoff UAR value. To determine independent predictors of mortality after TAVI, univariate and multivariate Cox regression analyses were used. Parameters with statistical significance in the univariate analysis were included in the subsequent multivariate analysis. A p value <0.05 was accepted as statistically significant.

Permanent pacemaker implantation due to new-onset atrioventricular complete block after the TAVI was performed in 25 (10.4%) patients. The rate of baseline right bundle branch block was significantly higher among the patients who developed new-onset atrioventricular complete block than among the patients who did not (34.8% vs. 12.9%, p=0.01). Valve-in-valve implantation due to severe aortic regurgitation was performed in eight (3.3%) patients.

Following TAVI, acute renal failure was determined in 28 (11.7%) patients, peripheral vascular damage (e.g., dissection, hematoma) in 32 (13.3%), ischemic stroke in six (2.5%), myocardial infarction in 10 (4.2%), and ascending aorta dissection in two (0.8%). In-hospital mortality occurred in 16 (6.7%) patients, whereas postdischarge all-cause mortality occurred in 41 (17.1%). Of 16 in-hospital deceased patients, two patients died due to stroke, two patients due to ascending aorta dissection, three patients due to myocardial infarction, three patients due to peripheral vascular damage, one patient due to nosocomial pneumonia, three patients due to decompensated heart failure/cardiogenic shock, and two patients due to an unknown cause. The two-year mortality rate was determined to be 15% (n=36).

When the demographic and clinical characteristics of the patients were compared, the rate of systolic heart failure was found to be higher in the mortality group compared to the survival group (43.9% vs. 25.1%, p=0.007). The demographic and clinical characteristics of the patients are shown in Table 1.

Table 1: Demographic and clinic characteristics of the patients

When the laboratory and echocardiographic data of the patients were compared, the albumin level was significantly lower and the UAR was significantly higher in the mortality group (p<0.001 and p=0.001, respectively). The laboratory and echocardiographic data of the patients are shown in Table 2.

Table 2: The laboratory and echocardiographic characteristics of the patients

The area under the curve (AUC), evaluated for determining the diagnostic power of UAR in predicting mortality, was 0.671 (confidence interval [CI]: 0.589-0.753, p<0.001). No significant difference was found between the AUC of albumin and the AUC of UAR (0.675 vs. 0.671, p=0.93). A UAR value >2.03 had 70.2% sensitivity and 60.1% specificity in predicting all-cause mortality.

In the Kaplan-Meier survival analysis, the survival period was significantly shorter in the group with a UAR >2.03 (46.9 months vs. 58.6 months, p<0.001, Figure 1).

Figure 1: Kaplan-Meier analysis comparing the survival periods in patients above and below the cut off value of UAR. UAR: Uric acid/albumin ratio.

In the univariate Cox regression analysis, systolic heart failure, platelet count, and a UAR >2.03 were found to be associated with mortality after TAVI. In the multivariate regression analysis, UAR >2.03 (hazard ratio=2.958, CI: 1.623-5.393, p<0.001) and platelet count (hazard ratio=0.996, CI: 0.992-1.000, p=0.05) remained as independent predictors for mortality after TAVI (Table 3).

Table 3: Cox regression analysis for identifying predictors of mortality following TAVI

In a study in 2016, Gaede et al.[22] evaluated the results of 15,050 patients who had undergone TAVI and reported an in-hospital mortality rate of 2.6% and a permanent pacemaker implantation rate of 11.4%. Additionally, in this study, a cerebrovascular event was observed in 2.2%, vascular complications in 7.1%, myocardial infarction in 0.2%, and acute renal damage in 3%. Compared to the results of the current study, the lower rates of vascular complications, in-hospital mortality, and acute renal damage can be considered to be due to a difference in the experience of the operators and different study populations. In a 2013 study by Finkelstein et al.,[23] the outcomes of 300 TAVI patients were reported and in-hospital mortality, stroke, minor vascular complication, and permanent peacemaker implantation rates were 2.3%, 1.6%, 10.7%, and 22%, respectively. Although the in-hospital mortality rate was low compared to the rate in the current study, the high rate of permanent pacemaker implantation could have been due to the use of older generation bioprosthetic valves. Gleason et al.[3] evaluated patients implanted with a self-expandable valve, and found the five-year mortality rate after TAVI to be 55.3%. The significantly higher mortality could be attributed to the difference in the study populations and the shorter follow-up period in that study.

The current study results showed a low platelet count to be an independent predictor of mortality following TAVI. In parallel to the current study results, Kalińczuk et al.[24] also reported that a reduced platelet count after TAVI was associated with increased mortality. In another study, the development of thrombocytopenia after TAVI was found to be a predictor of 30-day mortality, and platelet count before the TAVI was the only predictor of thrombocytopenia.[25] Similarly, it can be considered that a lower thrombocyte count in the current study may have increased the risk of thrombocytopenia development after TAVI. However, there is a need for further studies on this subject.

In a previous meta-analysis, the baseline albumin level was found to be an independent predictor of 30-day and one-year mortality after TAVI.[4] This finding is compatible with the finding of the current study that the albumin level was significantly lower in the mortality group. The mounting evidence indicating that low albumin level is related to endothelial dysfunction, subclinical systemic inflammation, and renal and liver dysfunction could explain the increased mortality in TAVI patients. Moreover, a decreased albumin level causes decreased intravascular osmotic colloidal pressure, which may accelerate the development of acute renal damage, pulmonary edema, or decompensated heart failure in TAVI patients.[5,26,27]

In a study by Sokmen et al.,[1] although the baseline uric acid level was significantly higher in patients who deceased after TAVI, it was not found to be an independent predictor of mortality. It has been previously stated that a high uric acid level is associated with increased inflammation, renin-angiotensin aldosterone activation, endothelial dysfunction, and aorta dilatation.[13,14,28]

To minimize the effect of the confounding factors on uric acid and albumin levels, these two markers were combined in the current study. Evidence related to the prognostic importance of uric acid and albumin levels may explain why the ratio of these two markers is a predictor of mortality following TAVI.

This study has several limitations. This study was retrospective in design, was conducted in only two centers, and the number of patients included was relatively limited. The scores other than the logistic EuroSCORE were not evaluated. Only four types of bioprosthetic valves were preferred so there was no experience with other bioprosthetic valves (e.g., Myval). When evaluating UAR and platelet count, only preprocedural blood results were used. Therefore, the effects of change in UAR and platelet count could not be investigated.

In conclusion, UAR, an easy-to-obtain and practical marker, was found to be an independent predictor of mortality after TAVI. Therefore, it would be appropriate to investigate the value of this marker with more evidence-based research methods to determine the risk of death in TAVI patients.

Ethics Committee Approval: The study protocol was approved by the University of Health Sciences, Bursa Yüksek Ihtisas Training and Research Hospital Ethics Committee (date: 02.11.2022, no: 2011-KAEK-25 2022/11-15). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept, design, data collection and processing, analysis and interpretation, writing the article, materials: F.L.; Idea/concept, control /supervision, data collection and processing, literature review, writing the article, critical review, references and fundings: İ.G.; Design, writing the article, materials: F.K.; Control/supervision, literature review, references and fundings: O.Ş.; Analysis and interpretation, critical review; S.A.S.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

1) Sokmen A, Aksu E, Cagri Aykan A, Sokmen G, Gunes H, Serhat Balcioglu A, et al. Predictors of mortality after transcatheter aortic valve implantation . Annals of Medical Research 2021;27:2014-21.

2) Arora S, Misenheimer JA, Ramaraj R. Transcatheter aortic valve replacement: Comprehensive review and present status. Tex Heart Inst J 2017;44:29-38. doi: 10.14503/THIJ-16-5852.

3) Gleason TG, Reardon MJ, Popma JJ, Deeb GM, Yakubov SJ, Lee JS, et al. 5-year outcomes of self-expanding transcatheter versus surgical aortic valve replacement in high-risk patients. J Am Coll Cardiol 2018;72:2687-96. doi:10.1016/j.jacc.2018.08.2146.

4) Liu G, Hu X, Long M, Du ZM, Li Y, Hu CH. Meta-analysis of the impact of pre-procedural serum albumin on mortality in patients undergoing transcatheter aortic valve replacement. Int Heart J 2020;61:67-76. doi: 10.1536/ihj.19-395.

5) Fanali G, di Masi A, Trezza V, Marino M, Fasano M, Ascenzi P. Human serum albumin: From bench to bedside. Mol Aspects Med 2012;33:209-90. doi: 10.1016/j. mam.2011.12.002.

6) Leite HP, Rodrigues da Silva AV, de Oliveira Iglesias SB, Koch Nogueira PC. Serum albumin is an independent predictor of clinical outcomes in critically ill children. Pediatr Crit Care Med 2016;17:e50-7. doi: 10.1097/ PCC.0000000000000596.

7) Kittisakmontri K, Reungrongrat S, Lao-Araya M. Hypoalbuminaemia at admission predicts the poor outcomes in critically ill children. Anaesthesiol Intensive Ther 2016;48:158-61. doi: 10.5603/AIT.a2016.0028.

8) Fleck A, Raines G, Hawker F, Trotter J, Wallace PI, Ledingham IM, et al. Increased vascular permeability: A major cause of hypoalbuminaemia in disease and injury. Lancet 1985;1:781-4. doi: 10.1016/s0140- 6736(85)91447-3.

9) Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: Meta-analyses of prospective studies. JAMA 1998;279:1477-82. doi: 10.1001/ jama.279.18.1477.

10) Shao M, Wang S, Parameswaran PK. Hypoalbuminemia: A risk factor for acute kidney injury development and progression to chronic kidney disease in critically ill patients. Int Urol Nephrol 2017;49:295-302. doi: 10.1007/ s11255-016-1453-2.

11) Griebsch A, Zöllner N. Effect of ribomononucleotides given orally on uric acid production in man. Adv Exp Med Biol 1974;41:443-9. doi: 10.1007/978-1-4757-1433-3_9.

12) Sorensen LB, Levinson DJ. Origin and extrarenal elimination of uric acid in man. Nephron 1975;14:7-20. doi:10.1159/000180432.

13) Ruggiero C, Cherubini A, Ble A, Bos AJ, Maggio M, Dixit VD, et al. Uric acid and inflammatory markers. Eur Heart J 2006;27:1174-81. doi: 10.1093/eurheartj/ehi879.

14) Mehta T, Nuccio E, McFann K, Madero M, Sarnak MJ, Jalal D. Association of uric acid with vascular stiffness in the Framingham heart study. Am J Hypertens 2015;28:877-83. doi: 10.1093/ajh/hpu253.

15) Cai J, Zhang Y, Zou J, Shen Y, Luo D, Bao H, et al. Serum uric acid could be served as an independent marker for increased risk and severity of ascending aortic dilatation in Behçet's disease patients. J Clin Lab Anal 2019;33:e22637. doi: 10.1002/jcla.22637.

16) Virdis A, Masi S, Casiglia E, Tikhonoff V, Cicero AFG, Ungar A, et al. Identification of the uric acid thresholds predicting an increased total and cardiovascular mortality over 20 years. Hypertension 2020;75:302-8. doi: 10.1161/ HYPERTENSIONAHA.119.13643.

17) Kleber ME, Delgado G, Grammer TB, Silbernagel G, Huang J, Krämer BK, et al. Uric acid and cardiovascular events: A Mendelian randomization study. J Am Soc Nephrol 2015;26:2831-8. doi: 10.1681/ASN.2014070660.

18) Tomita M, Mizuno S, Yamanaka H, Hosoda Y, Sakuma K, Matuoka Y, et al. Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol 2000;10:403-9. doi: 10.2188/jea.10.403.

19) Özgür Y, Akın S, Yılmaz NG, Gücün M, Keskin Ö. Uric acid albumin ratio as a predictive marker of short-term mortality in patients with acute kidney injury. Clin Exp Emerg Med 2021;8:82-8. doi: 10.15441/ceem.20.024.

20) Wang X, Deng C, Guo F, Zhong L, Li M, Xue Y, et al. Preoperative uric acid-to-albumin ratio as a new indicator for predicting long-term prognosis in patients with acute type a aortic dissection. Research Square 2022. doi:10.21203/rs.3.rs-1281513/v1.

21) Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. doi: 10.7326/0003-4819-130-6- 199903160-00002.

22) Gaede L, Blumenstein J, Liebetrau C, Dörr O, Kim WK, Nef H, et al. Outcome after transvascular transcatheter aortic valve implantation in 2016. Eur Heart J 2018;39:667-75. doi:10.1093/eurheartj/ehx688.

23) Finkelstein A, Birati EY, Abramowitz Y, Steinvil A, Sheinberg N, Biner S, et al. Transcatheter aortic valve implantation: A single-center experience of 300 cases. Isr Med Assoc J 2013;15:613-6.

24) Kalińczuk Ł, Zieliński K, Chmielak Z, Mintz GS, Dąbrowski M, Pręgowski J, et al. Effect on mortality of systemic thromboinflammatory response after transcatheter aortic valve implantation. Am J Cardiol 2019;124:1741-7. doi:10.1016/j.amjcard.2019.08.036.

25) Kyranis SJ, Markiham R, Savage M, Crowhurst J, Murdoch D, Poon K, et al. Thrombocytopenia post transcatheter aortic valve insertion: Clinical and prognostic significance. Structural Heart 2019;3:150-4. doi:10.1080/24748706.2019.1569794.

26) Lee EH, Baek SH, Chin JH, Choi DK, Son HJ, Kim WJ, et al. Preoperative hypoalbuminemia is a major risk factor for acute kidney injury following off-pump coronary artery bypass surgery. Intensive Care Med 2012;38:1478-86. doi:10.1007/s00134-012-2599-8.

27) Arquès S, Ambrosi P, Gélisse R, Luccioni R, Habib G. Hypoalbuminemia in elderly patients with acute diastolic heart failure. J Am Coll Cardiol 2003;42:712-6. doi: 10.1016/ s0735-1097(03)00758-7.

28) Esen AM, Akcakoyun M, Esen O, Acar G, Emiroglu Y, Pala S, et al. Uric acid as a marker of oxidative stress in dilatation of the ascending aorta. Am J Hypertens 2011;24:149-54. doi: 10.1038/ajh.2010.219.