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Renal impairment and outcome in patients with takotsubo cardiomyopathy
American Journal of Emergency Medicine 34 (2016) 548–552
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Renal impairment and outcome in patients with takotsubo cardiomyopathy Francesco Santoro, MD a, Armando Ferraretti, MD a, Riccardo Ieva, MD a, Francesco Musaico, MD a, Mario Fanelli, MD a, Nicola Tarantino, MD a, Maria Scarcia, MD a, Pasquale Caldarola, MD b, Matteo Di Biase, MD a, Natale Daniele Brunetti, MD, PhD a,⁎ a b
University of Foggia, Italy San Paolo Hospital, Bari, Italy
a r t i c l e
i n f o
Article history: Received 6 November 2015 Received in revised form 20 December 2015 Accepted 22 December 2015
a b s t r a c t Objectives: The objectives were to ascertain the prevalence of renal impairment among patients with a takotsubo cardiomyopathy (TTC) episode and whether clinical outcomes are related to renal function. Methods: A total of 108 consecutive subjects with TTC were enrolled in a multicenter registry and followed for a mean period of 429 days. Renal function was evaluated during hospitalization in terms of acute kidney injury/ failure and estimated glomerular filtration rate (eGFR). Incidence of death, rehospitalization, and recurrence of TTC during follow-up was recorded. Results: Raised creatinine levels can be found during hospitalizations for TTC episodes (analysis of variance P b .001). Incidence of acute kidney injury was 10%; that of acute kidney failure was 1%. Admission eGFR levels were proportional to the duration of hospitalization (r = −0.28, P b .01). Estimated GFR nadir values were related to adverse events at follow-up (log-rank P b .001). The hazard ratio of adverse events at follow-up in subjects with severe renal impairment (nadir eGFR b30 mL/[min 1.73 m2]) vs those with eGFR N 60 mL/(min 1.73 m2) was 1.817 (95% confidence interval, 1.097-3.009; P b .05). Conclusions: Raised creatinine levels and impaired renal function may be found in patients with TTC. Lower eGFR values during hospitalization are associated with longer hospitalizations and higher rates of adverse events at follow-up. Renal function during a TTC episode should be carefully evaluated. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Methods
Renal function has been found to be an independent risk factor for cardiovascular (CV) outcome in patients with heart failure (HF) with either preserved or reduced ejection fraction [1]. About 63% of patients with HF have renal impairment [2]. Furthermore, worsening of renal function is common among hospitalized HF patients and is significantly related with higher mortality rates [3]. Takotsubo cardiomyopathy (TTC) is an acute and reversible form of HF [4] that can mimic acute myocardial infarction. Several algorithms based on the use of electrocardiogram and/or biomarkers have been proposed for the diagnostic workup of TTC [5,6], but no studies have evaluated renal function and its prognostic role among patients admitted for TTC. The aim of the study was therefore to evaluate renal function and its potential prognostic role in this context.
2.1 Study population
⁎ Corresponding author at: Viale Pinto n.1 71100, Foggia, Italy. Tel.: +39 3389112358; fax: +39 0881745424. E-mail address: [email protected] (N.D. Brunetti). http://dx.doi.org/10.1016/j.ajem.2015.12.065 0735-6757/© 2015 Elsevier Inc. All rights reserved.
We prospectively evaluated 108 consecutive patients with a diagnosis of TTC from July 2007 to May 2014 enrolled in a multicenter registry covering 3 hospitals, an Italian area of one and half million inhabitants (University Hospital of Foggia; “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo; and “San Paolo” Hospital, Bari, Italy). 2.2 Inclusion criteria The diagnosis of TTC was based on Mayo Clinic criteria:(a) transient hypokinesis, akinesis, or dyskinesis of the left ventricular (LV) mid segments, with or without apical involvement; the regional wall-motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always, present; (b) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (c) new electrocardiographic abnormalities, ST-segment elevation and/or T-wave inversion, or modest elevation in cardiac troponin; and (d) absence of pheochromocytoma and myocarditis [7].
F. Santoro et al. / American Journal of Emergency Medicine 34 (2016) 548–552
2.3 Clinical and echocardiographic examination All patients underwent a clinical examination, and age, sex, medical history, kind of stressors, and electrocardiographic presentation were recorded. A 2-dimensional Doppler echocardiographic examination on the day of admission, at the third day, and at discharge was performed. The LV ejection fraction (LVEF) was calculated using the Simpson method from the apical 4-chamber and 2-chamber view [8]. 2.4 Blood sample collection Circulating levels of troponin I, blood urea nitrogen (BUN), and creatinine were obtained by venipuncture at the admission; at the second, third, and fourth day during hospitalization; and at discharge. Normal values were as follows: b0.5 ng/mL for cardiac troponin-I, 10-50 mg/dL for BUN, and 0.61-1.24 mg/dL for creatinine. 2.5 Renal function evaluation Degree of renal impairment was classified according to the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure criteria [9]. Acute kidney injury (AKI) is defined as creatinine levels 2 times higher than the admission value or estimated glomerular filtration rate (eGFR) decrease N 50%; acute renal failure is defined as creatinine levels are 3 times higher than the admission value or eGFR decrease N 75%. Estimated glomerular filtration rate was calculated through the use of the 4-component Modification of Diet in Renal Disease study equation incorporating age, race, sex, and serum creatinine level: eGFR =186 × (serum creatinine level [in mg/dL] −1.154) × (age [in years] −0.203). For women and blacks, the product of this equation was multiplied by a correction factor of 0.742 and 1.21, respectively [10]. According with the Kidney Disease Outcomes Quality Initiative classification of the stages of chronic kidney disease [11], patients were divided into 3 groups following an evaluation of the eGFR (group 1: “normal-mild renal impairment,” eGFR N 60 mL/[min 1.73 m 2]; group 2: “moderate renal impairment,” eGFR from 60 to 30 mL/[min 1.73 m 2]; group 3: “severe renal impairment,” eGFR b 30 mL/[min 1.73 m2]). Estimated GFR nadir was defined as the lowest value of eGFR observed during hospitalization. 2.6 Follow-up and definition of outcome Complete follow-up data were available in all 108 patients with a follow-up of at least 3 months from the time of study inclusion. Patients were scheduled for clinical and echocardiographic examinations at the cardiomyopathy ambulatory of the cardiology department (3 months after TTC episode and every 9 months). Clinical end points included total mortality, CV mortality (sudden and nonsudden CV death), TTC recurrence, and hospitalization for any CV cause. These clinical end points were recorded and evaluated as adverse events at follow-up. All patients gave a written informed consent; the study was approved by local ethical committees. 2.7 Statistical analysis Continuous variables were reported as means ± standard deviation and compared with Student t test for either paired or unpaired groups as required; dichotomic variables were reported as percentage and compared with χ2 test of Fisher test as required. Normal distribution of variables was tested with Kolmogorov-Smirnov and Lilliefors test; correlations were therefore analyzed with Pearson or Spearman test as required. Repeated measures were analyzed with analysis of variance test (ANOVA). Survival rate was reported on Kaplan-Meier plot and analyzed with log-rank test and multiple stepwise Cox analysis, which was used for
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calculation of hazard ratio with 95% confidence intervals (CIs). Receiver operating characteristic curves were reported and compared with Hanley and McNeil method. A P value b.05 was considered as statistically significant. 3. Results 3.1 Baseline features One hundred and eight consecutive subjects with TTC were enrolled in the study and followed up for a mean period of 429 ± 601 days. Mean population age was 72.7 ± 10.5 years, 7% were male (n = 8), 78% had hypertension, 41% had dyslipidemia, 24% were obese, 14% were smokers, and 27% were diabetic. Mean hospital stay was 8 ± 3.5 days. Twenty-eight percent had an emotional stressor; 43%, physical; and 29%, no reported stressor. Clinical presentation of TTC episodes was typical angina in 52% of patients, atypical chest pain in 17%, and no chest pain in 28% (Table 1). During follow-up period, 18% incurred adverse events (9% death, 5% TTC recurrence, 4% rehospitalization). Creatinine levels significantly rose up during hospitalization as shown in Fig. 1 (ANOVA P b .001). Peak creatinine levels during hospitalization were significantly higher than those on admission (1.42 ± 1.13 vs 1.05 ± 0.78 mg/dL, P b .001). 3.2 Acute renal impairment Incidence of AKI as described above was 10% (11 patients); that of acute kidney failure as described above was 1% (1 patient). Subjects who developed AKI were significantly different from those without as for diabetes (43% vs 23%, P b .05) and LVEF at admission (30% ± 7% vs 37% ± 9%, P b .05). Furthermore, subject who developed AKI had a longer hospitalization (10 ± 3.3 days vs 7.8 ± 3.4 days, P b .05) and required inotropes infusion; in all cases, patients received levosimendan infusion [12] (45% vs 14%, P b .05). 3.3 eGFR, hospitalization, and follow-up The duration of hospitalization was proportional to eGFR values at admission (r = −0.28, P b .01, Fig. 2).
Table 1 Baseline and hospitalization features of patients admitted with a diagnosis of TTC No. of pts. = 108
Mean
Age Male Hypertension Dyslipidemia Obesity Smoker Diabetes Pneumologic disease Hospitalization days No chest pain Typical chest pain Atypical chest pain Dyspnea Emotional stressor Physical stressor No stressor EF at admission EF at discharge Troponin I levels at admission Troponin I levels at discharge BUN levels at admission BUN levels at discharge Creatinine levels at admission Creatinine levels at discharge Creatinine peak during hospitalization eGFR at admission eGFR nadir
72.7 ± 10.5 7% 78% 41% 24% 14% 27% 23% 8.06 ± 3.49 28% 52% 17% 32% 28% 43% 29% 36% ± 9% 50% ± 7% 4.48 ± 11.10 ng/mL 0.33 ± 0.67 ng/mL 53.50 ± 28.67 mg/dL 76.49 ± 37.47 mg/dL 1.05 ± 0.79 mg/dL 1.23 ± 0.62 mg/dL 1.42 ± 1.13 mg/dL 74.16 ± 33.64 mL/(min 1.73 m2) 56.19 ± 29.15 mL/(min 1.73 m2)
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F. Santoro et al. / American Journal of Emergency Medicine 34 (2016) 548–552
ratio of adverse events at follow-up at Cox survival analysis was 1.817 (95% CI, 1.097-3.009; P b .05) for subjects with severe renal impairment (nadir eGFRb 30 mL/[min 1.73 m 2]) vs those with eGFR N60 mL/[min 1.73 m 2]), 1.49 (95% CI, 1.019-2.181; P b .05) for every 20 mL/(min 1.73 m 2) of reduction in eGFR values below 100 mL/(min 1.73 m2). 4. Discussion
Fig. 1. Dynamic evolution of creatinine levels during hospitalization (ANOVA P b .001).
To the best of our knowledge, this is the first study evaluating renal function and its prognostic role among patients admitted with TTC. Renal (dys)function during a TTC episode, in terms of eGFR and AKI, showed several prognostic implications. Acute renal injury was related to longer hospitalizations and higher need for inotrope infusion. Admission eGFR values were directly related to duration of hospitalization, whereas eGFR nadir values b30 mL/(min 1.73 m 2) during hospitalization were associated with high rates of adverse events during hospitalization and at the follow-up. 4.1 Renal function and CV outcome
Fig. 2. Correlation between admission levels of eGFR and hospital stay.
According to eGFR nadir values during hospitalization, patients were divided into 3 groups as reported in Table 2. The rates of incidence of adverse event were related to eGFR nadir values and exactly 13% in subjects (n = 45) with eGFR N60 mL/(min 1.73 m2), 14% in those (n = 43) with eGFR between 60 and 30 mL/(min 1.73 m2), and 40% in those (n = 20) with eGFR b 30 mL/(min 1.73 m2) (P b .05 vs both other groups) (Fig. 3). At survival free from adverse event analysis, the prognosis was progressively poorer in subjects with eGFR N 60 mL/(min 1.73 m 2), those with eGFR between 30 and 60 mL/(min 1.73 m 2), and finally those with eGFR b30 mL/(min 1.73 m 2) (log-rank P b .01) (Fig. 4). The hazard
The relationship between renal function and CV outcome has been widely proved in several different settings of patients. Henry et al [13] found in a middle-aged population without CV disease that even mild kidney disease may be associated with CV outcomes. These findings were also confirmed in patients with CV disease such as myocardial infarction and congestive HF. In populations of patients with a prior acute myocardial infarction, the risk of death and adverse events was increased with declining estimated GFRs values. Below 81.0 mL/(min 1.73 m 2), each reduction of the estimated GFR by 10 units was associated with a risk for death and nonfatal CV outcomes of 1.10 [14]. Moreover, in patients with congestive HF irrespective of their ejection fraction [1], the risk of CV death or rehospitalization increased significantly below an eGFR of 60 mL/(min 1.73 m2). Renal impairment, during the first hospital admission for HF with preserved ejection fraction, influences long-term outcome. Lower eGFR values (b 60 mL/[min 1.73 m2]) confer an increased risk of overall and CV mortality during 7-year follow-up (35% for all-cause death and 42% for death from CV causes) [15]. Our data are in line with such results, especially when lower eGFR values are present; eGFR values b 30 mL/(min 1.73 m 2) identify a subgroup of patients at risk for adverse events at follow-up among patients with TTC. The ability of eGFR in identifying subjects at risk for adverse events at follow-up, beyond possible corrections for potential bias in multivariate analysis, is probably justified by the fact that eGFR includes variables usually considered in common multivariate analysis such as age, race, and sex, which may account for the efficacy of eGFR in stratifying the risk in subjects with TTC.
Table 2 Baseline features, and events during hospitalization and at follow-up stratified for eGFR nadir values during hospitalization for a TTC episode
Age Male Hypertension Dyslipidemia Obesity Smoker Diabetes Pulmonary disease Emotional stress Physical stress No stress Hospitalization days Adverse events at follow-up
eGFR: N60
eGFR: 60-30
eGFR: b30
P
P
P
(n = 45)
(n = 43)
(n = 20)
N60 vs 60-30
N60 vs b30
60-30 vs b30
66.91 ± 10.32 2% 64% 40% 27% 16% 20% 9% 40% 31% 29% 6.8 ± 2.6 13%
75.12 ± 8.20 5% 91% 35% 26% 14% 26% 29% 23% 49% 30% 8.2 ± 3.5 14%
81.50 ± 7.29 25% 85% 55% 15% 10% 45% 40% 10% 60% 30% 10.6 ± 3.6 40%
.001 .535 .002 .624 .909 .834 .537 .031 .093 .091 .891 .049 .933
.001 .002 .095 .268 .310 .556 .038 .004 .015 .028 .928 .001 .015
.004 .016 .510 .135 .355 .667 .127 .394 .218 .417 .985 .016 .020
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previously described cases of acute renal failure combined with digoxin toxicity and bradyarrhythmia as a possible trigger of TTC [25]. The role of renal dysfunction in the mechanism of TTC is still unclear but may probably represent a comorbidity such as malignancy, rheumatic disease, sepsis [26], pneumonia, and cerebrovascular diseases [27] that should be considered for risk stratification in patients with TTC. 4.3. Limitations
Fig. 3. Estimated GFR nadir values during hospitalization and incidence of adverse events at follow-up.
These are preliminary results to be confirmed in larger cohorts of patients. Further and more adequately powered prospective studies are warranted to clarify the assay standardization, the optimal cutoff, and the prognostic value of eGFR in association with other biomarkers and clinical scores. Contrast-induced nephropathy may have been related to the incidence of adverse events and hospital stay; however, because all subjects enrolled in the study underwent coronary angiography at admission and therefore contrast-induced nephropathy is impossible to distinguish from acute worsening of renal failure linked with TTC, the effect of contrast-induced nephropathy may be hypothesized but not exactly quantified. 5. Conclusions
The mechanisms by which renal impairment may be associated with a poorer outcome are not completely clear. Renal dysfunction could reflect a more generalized vascular disease and a wide range of comorbidities [16,17]. Furthermore, increased levels of biomarkers associated with both HF and diffuse serosal effusion could be present even in patient with TTC. Indeed, we found that CA-125, a tumor biomarker produced by mesothelial cells from the pleura, pericardium, and peritoneum, could be used as predictor of adverse events at follow-up with 80% of sensitivity and 76% of specificity [18].
4.2. Kidney dysfunction and TTC Higher levels of catecholamines, the main driver of TTC [19], have been found in end-stage renal disease. Elias et al [20] showed how elevated plasma concentrations of norepinephrine and dopamine were significantly elevated in patients with end-stage renal disease undergoing maintenance hemodialysis and slightly decreased by hemodyalisis [21]. More recently, Shin et al [22] described a case series of 7 patients with renal dysfunction who experienced a TTC episode. Three of these patients were on maintenance hemodialysis, and 4 patients had AKI. TTC has also been reported during peritoneal dialysis [23,24]. We have
Fig. 4. Kaplan-Meier curves showing adverse events at follow-up according to eGFR nadir values during hospitalization (log-rank P b .01).
Raised creatinine levels and impaired renal function may be found in patients with TTC. Lower eGFR values during hospitalization for TTC are associated with longer hospital stay and high rates of adverse events at follow-up. Disclosures No conflict of interest to disclose. References [1] Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, et al. Candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) investigators. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006;113:671–8. [2] Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006;47:1987–96. [3] Forman DE, Butler J, Wang Y, Abraham WT, O'Connor CM, Gottlieb SS, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004;43:61–7. [4] Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. . Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270–6. [5] Kosuge M, Ebina T, Hibi K, Morita S, Okuda J, Iwahashi N, et al. Simple and accurate electrocardiographic criteria to differentiate takotsubo cardiomyopathy from anterior acute myocardial infarction. J Am Coll Cardiol 2010;55:2514–6. [6] Randhawa MS, Dhillon AS, Taylor HC, Sun Z, Desai MY. Diagnostic utility of cardiac biomarkers in discriminating takotsubo cardiomyopathy from acute myocardial infarction. J Card Fail 2014;20:2–8. [7] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J 2008;155: 408–17. [8] Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [9] Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney Int 2008;73:538–46. [10] 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. [11] Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National kidney foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137–47. [12] Santoro F, Ieva R, Ferraretti A, Ienco V, Carpagnano G, Lodispoto M, et al. Safety and feasibility of levosimendan administration in takotsubo cardiomyopathy: a case series. Cardiovasc Ther 2013;31:e133–7. [13] Henry RM, Kostense PJ, Bos G, Dekker JM, Nijpels G, Heine RJ, et al. Mild renal insufficiency is associated with increased cardiovascular mortality: the Hoorn study. Kidney Int 2002;62:1402–7.
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[14] Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285–95. [15] Rusinaru D, Buiciuc O, Houpe D, Tribouilloy C. Renal function and long-term survival after hospital discharge in heart failure with preserved ejection fraction. Int J Cardiol 2011;147:278–82. [16] Li X, Hassoun HT, Santora R, Rabb H. Organ crosstalk: the role of the kidney. Curr Opin Crit Care 2009;15:481–7. [17] Yap SC, Lee HT. Acute kidney injury and extrarenal organ dysfunction: new concepts and experimental evidence. Anesthesiology 2012;116:1139–48. [18] Santoro F, Ferraretti A, Musaico F, Di Martino L, Ieva R, Di Biase M, et al. Increased levels of carbohydrate-antigen-125 at admission predicts hospital stay and incidence of adverse events in stress cardiomyopathy. Eur Heart J 2014;35(Abstract Supplement):1094. [19] Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539–48. [20] Elias AN, Vaziri ND, Maksy M. Plasma norepinephrine, epinephrine, and dopamine levels in end-stage renal disease. Effect of hemodialysis. Arch Intern Med 1985;145:1013–5.
[21] Masuo K, Mikami H, Ogihara T, Tuck M. Hormonal mechanisms in blood pressure reduction during hemodialysis in patients with chronic renal failure. Hypertens Res 1995;18(Suppl. 1):S201–3. [22] Shin MJ, Rhee H, Kim IY, Yang BY, Song SH, Lee DW, et al. Clinical features of patients with stress-induced cardiomyopathy associated with renal dysfunction: 7 case series in single center. BMC Nephrol 2013;14:213. [23] Musone D, Nicosia V, D'Alessandro R, Treglia A, Montella M, Saltarelli G, et al. Acute heart failure secondary to takotsubo cardiomyopathy in a patient on peritoneal dialysis with residual renal function loss. G Ital Nefrol 2012;29:467–72. [24] Hassan S, Hassan F, Hassan D, Hassan S, Hassan K. Takotsubo cardiomyopathy associated with peritonitis in peritoneal dialysis patient. Ren Fail 2011;33:904–7. [25] Santoro F, Ieva R, Ferraretti A, Carpagnano G, Lodispoto M, De Gennaro L, et al. Acute renal failure, digoxin toxicity and brady-arrhythmia as possible triggers in takotsubo cardiomyopathy. Int J Cardiol 2013;165:e51–2. [26] Santoro F, Di Biase M, Brunetti ND. Urinary sepsis associated with takotsubo cardiomyopathy. Int J Urol 2014;21:432–3. [27] Santoro F, Carapelle E, Cieza Ortiz SI, Musaico F, Ferraretti A, d'Orsi G, et al. Potential links between neurological disease and tako-tsubo cardiomyopathy: a literature review. Int J Cardiol 2013;168:688–91.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Renal impairment and outcome in patients with takotsubo cardiomyopathy Francesco Santoro, MD a, Armando Ferraretti, MD a, Riccardo Ieva, MD a, Francesco Musaico, MD a, Mario Fanelli, MD a, Nicola Tarantino, MD a, Maria Scarcia, MD a, Pasquale Caldarola, MD b, Matteo Di Biase, MD a, Natale Daniele Brunetti, MD, PhD a,⁎ a b
University of Foggia, Italy San Paolo Hospital, Bari, Italy
a r t i c l e
i n f o
Article history: Received 6 November 2015 Received in revised form 20 December 2015 Accepted 22 December 2015
a b s t r a c t Objectives: The objectives were to ascertain the prevalence of renal impairment among patients with a takotsubo cardiomyopathy (TTC) episode and whether clinical outcomes are related to renal function. Methods: A total of 108 consecutive subjects with TTC were enrolled in a multicenter registry and followed for a mean period of 429 days. Renal function was evaluated during hospitalization in terms of acute kidney injury/ failure and estimated glomerular filtration rate (eGFR). Incidence of death, rehospitalization, and recurrence of TTC during follow-up was recorded. Results: Raised creatinine levels can be found during hospitalizations for TTC episodes (analysis of variance P b .001). Incidence of acute kidney injury was 10%; that of acute kidney failure was 1%. Admission eGFR levels were proportional to the duration of hospitalization (r = −0.28, P b .01). Estimated GFR nadir values were related to adverse events at follow-up (log-rank P b .001). The hazard ratio of adverse events at follow-up in subjects with severe renal impairment (nadir eGFR b30 mL/[min 1.73 m2]) vs those with eGFR N 60 mL/(min 1.73 m2) was 1.817 (95% confidence interval, 1.097-3.009; P b .05). Conclusions: Raised creatinine levels and impaired renal function may be found in patients with TTC. Lower eGFR values during hospitalization are associated with longer hospitalizations and higher rates of adverse events at follow-up. Renal function during a TTC episode should be carefully evaluated. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Methods
Renal function has been found to be an independent risk factor for cardiovascular (CV) outcome in patients with heart failure (HF) with either preserved or reduced ejection fraction [1]. About 63% of patients with HF have renal impairment [2]. Furthermore, worsening of renal function is common among hospitalized HF patients and is significantly related with higher mortality rates [3]. Takotsubo cardiomyopathy (TTC) is an acute and reversible form of HF [4] that can mimic acute myocardial infarction. Several algorithms based on the use of electrocardiogram and/or biomarkers have been proposed for the diagnostic workup of TTC [5,6], but no studies have evaluated renal function and its prognostic role among patients admitted for TTC. The aim of the study was therefore to evaluate renal function and its potential prognostic role in this context.
2.1 Study population
⁎ Corresponding author at: Viale Pinto n.1 71100, Foggia, Italy. Tel.: +39 3389112358; fax: +39 0881745424. E-mail address: [email protected] (N.D. Brunetti). http://dx.doi.org/10.1016/j.ajem.2015.12.065 0735-6757/© 2015 Elsevier Inc. All rights reserved.
We prospectively evaluated 108 consecutive patients with a diagnosis of TTC from July 2007 to May 2014 enrolled in a multicenter registry covering 3 hospitals, an Italian area of one and half million inhabitants (University Hospital of Foggia; “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo; and “San Paolo” Hospital, Bari, Italy). 2.2 Inclusion criteria The diagnosis of TTC was based on Mayo Clinic criteria:(a) transient hypokinesis, akinesis, or dyskinesis of the left ventricular (LV) mid segments, with or without apical involvement; the regional wall-motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always, present; (b) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (c) new electrocardiographic abnormalities, ST-segment elevation and/or T-wave inversion, or modest elevation in cardiac troponin; and (d) absence of pheochromocytoma and myocarditis [7].
F. Santoro et al. / American Journal of Emergency Medicine 34 (2016) 548–552
2.3 Clinical and echocardiographic examination All patients underwent a clinical examination, and age, sex, medical history, kind of stressors, and electrocardiographic presentation were recorded. A 2-dimensional Doppler echocardiographic examination on the day of admission, at the third day, and at discharge was performed. The LV ejection fraction (LVEF) was calculated using the Simpson method from the apical 4-chamber and 2-chamber view [8]. 2.4 Blood sample collection Circulating levels of troponin I, blood urea nitrogen (BUN), and creatinine were obtained by venipuncture at the admission; at the second, third, and fourth day during hospitalization; and at discharge. Normal values were as follows: b0.5 ng/mL for cardiac troponin-I, 10-50 mg/dL for BUN, and 0.61-1.24 mg/dL for creatinine. 2.5 Renal function evaluation Degree of renal impairment was classified according to the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure criteria [9]. Acute kidney injury (AKI) is defined as creatinine levels 2 times higher than the admission value or estimated glomerular filtration rate (eGFR) decrease N 50%; acute renal failure is defined as creatinine levels are 3 times higher than the admission value or eGFR decrease N 75%. Estimated glomerular filtration rate was calculated through the use of the 4-component Modification of Diet in Renal Disease study equation incorporating age, race, sex, and serum creatinine level: eGFR =186 × (serum creatinine level [in mg/dL] −1.154) × (age [in years] −0.203). For women and blacks, the product of this equation was multiplied by a correction factor of 0.742 and 1.21, respectively [10]. According with the Kidney Disease Outcomes Quality Initiative classification of the stages of chronic kidney disease [11], patients were divided into 3 groups following an evaluation of the eGFR (group 1: “normal-mild renal impairment,” eGFR N 60 mL/[min 1.73 m 2]; group 2: “moderate renal impairment,” eGFR from 60 to 30 mL/[min 1.73 m 2]; group 3: “severe renal impairment,” eGFR b 30 mL/[min 1.73 m2]). Estimated GFR nadir was defined as the lowest value of eGFR observed during hospitalization. 2.6 Follow-up and definition of outcome Complete follow-up data were available in all 108 patients with a follow-up of at least 3 months from the time of study inclusion. Patients were scheduled for clinical and echocardiographic examinations at the cardiomyopathy ambulatory of the cardiology department (3 months after TTC episode and every 9 months). Clinical end points included total mortality, CV mortality (sudden and nonsudden CV death), TTC recurrence, and hospitalization for any CV cause. These clinical end points were recorded and evaluated as adverse events at follow-up. All patients gave a written informed consent; the study was approved by local ethical committees. 2.7 Statistical analysis Continuous variables were reported as means ± standard deviation and compared with Student t test for either paired or unpaired groups as required; dichotomic variables were reported as percentage and compared with χ2 test of Fisher test as required. Normal distribution of variables was tested with Kolmogorov-Smirnov and Lilliefors test; correlations were therefore analyzed with Pearson or Spearman test as required. Repeated measures were analyzed with analysis of variance test (ANOVA). Survival rate was reported on Kaplan-Meier plot and analyzed with log-rank test and multiple stepwise Cox analysis, which was used for
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calculation of hazard ratio with 95% confidence intervals (CIs). Receiver operating characteristic curves were reported and compared with Hanley and McNeil method. A P value b.05 was considered as statistically significant. 3. Results 3.1 Baseline features One hundred and eight consecutive subjects with TTC were enrolled in the study and followed up for a mean period of 429 ± 601 days. Mean population age was 72.7 ± 10.5 years, 7% were male (n = 8), 78% had hypertension, 41% had dyslipidemia, 24% were obese, 14% were smokers, and 27% were diabetic. Mean hospital stay was 8 ± 3.5 days. Twenty-eight percent had an emotional stressor; 43%, physical; and 29%, no reported stressor. Clinical presentation of TTC episodes was typical angina in 52% of patients, atypical chest pain in 17%, and no chest pain in 28% (Table 1). During follow-up period, 18% incurred adverse events (9% death, 5% TTC recurrence, 4% rehospitalization). Creatinine levels significantly rose up during hospitalization as shown in Fig. 1 (ANOVA P b .001). Peak creatinine levels during hospitalization were significantly higher than those on admission (1.42 ± 1.13 vs 1.05 ± 0.78 mg/dL, P b .001). 3.2 Acute renal impairment Incidence of AKI as described above was 10% (11 patients); that of acute kidney failure as described above was 1% (1 patient). Subjects who developed AKI were significantly different from those without as for diabetes (43% vs 23%, P b .05) and LVEF at admission (30% ± 7% vs 37% ± 9%, P b .05). Furthermore, subject who developed AKI had a longer hospitalization (10 ± 3.3 days vs 7.8 ± 3.4 days, P b .05) and required inotropes infusion; in all cases, patients received levosimendan infusion [12] (45% vs 14%, P b .05). 3.3 eGFR, hospitalization, and follow-up The duration of hospitalization was proportional to eGFR values at admission (r = −0.28, P b .01, Fig. 2).
Table 1 Baseline and hospitalization features of patients admitted with a diagnosis of TTC No. of pts. = 108
Mean
Age Male Hypertension Dyslipidemia Obesity Smoker Diabetes Pneumologic disease Hospitalization days No chest pain Typical chest pain Atypical chest pain Dyspnea Emotional stressor Physical stressor No stressor EF at admission EF at discharge Troponin I levels at admission Troponin I levels at discharge BUN levels at admission BUN levels at discharge Creatinine levels at admission Creatinine levels at discharge Creatinine peak during hospitalization eGFR at admission eGFR nadir
72.7 ± 10.5 7% 78% 41% 24% 14% 27% 23% 8.06 ± 3.49 28% 52% 17% 32% 28% 43% 29% 36% ± 9% 50% ± 7% 4.48 ± 11.10 ng/mL 0.33 ± 0.67 ng/mL 53.50 ± 28.67 mg/dL 76.49 ± 37.47 mg/dL 1.05 ± 0.79 mg/dL 1.23 ± 0.62 mg/dL 1.42 ± 1.13 mg/dL 74.16 ± 33.64 mL/(min 1.73 m2) 56.19 ± 29.15 mL/(min 1.73 m2)
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ratio of adverse events at follow-up at Cox survival analysis was 1.817 (95% CI, 1.097-3.009; P b .05) for subjects with severe renal impairment (nadir eGFRb 30 mL/[min 1.73 m 2]) vs those with eGFR N60 mL/[min 1.73 m 2]), 1.49 (95% CI, 1.019-2.181; P b .05) for every 20 mL/(min 1.73 m 2) of reduction in eGFR values below 100 mL/(min 1.73 m2). 4. Discussion
Fig. 1. Dynamic evolution of creatinine levels during hospitalization (ANOVA P b .001).
To the best of our knowledge, this is the first study evaluating renal function and its prognostic role among patients admitted with TTC. Renal (dys)function during a TTC episode, in terms of eGFR and AKI, showed several prognostic implications. Acute renal injury was related to longer hospitalizations and higher need for inotrope infusion. Admission eGFR values were directly related to duration of hospitalization, whereas eGFR nadir values b30 mL/(min 1.73 m 2) during hospitalization were associated with high rates of adverse events during hospitalization and at the follow-up. 4.1 Renal function and CV outcome
Fig. 2. Correlation between admission levels of eGFR and hospital stay.
According to eGFR nadir values during hospitalization, patients were divided into 3 groups as reported in Table 2. The rates of incidence of adverse event were related to eGFR nadir values and exactly 13% in subjects (n = 45) with eGFR N60 mL/(min 1.73 m2), 14% in those (n = 43) with eGFR between 60 and 30 mL/(min 1.73 m2), and 40% in those (n = 20) with eGFR b 30 mL/(min 1.73 m2) (P b .05 vs both other groups) (Fig. 3). At survival free from adverse event analysis, the prognosis was progressively poorer in subjects with eGFR N 60 mL/(min 1.73 m 2), those with eGFR between 30 and 60 mL/(min 1.73 m 2), and finally those with eGFR b30 mL/(min 1.73 m 2) (log-rank P b .01) (Fig. 4). The hazard
The relationship between renal function and CV outcome has been widely proved in several different settings of patients. Henry et al [13] found in a middle-aged population without CV disease that even mild kidney disease may be associated with CV outcomes. These findings were also confirmed in patients with CV disease such as myocardial infarction and congestive HF. In populations of patients with a prior acute myocardial infarction, the risk of death and adverse events was increased with declining estimated GFRs values. Below 81.0 mL/(min 1.73 m 2), each reduction of the estimated GFR by 10 units was associated with a risk for death and nonfatal CV outcomes of 1.10 [14]. Moreover, in patients with congestive HF irrespective of their ejection fraction [1], the risk of CV death or rehospitalization increased significantly below an eGFR of 60 mL/(min 1.73 m2). Renal impairment, during the first hospital admission for HF with preserved ejection fraction, influences long-term outcome. Lower eGFR values (b 60 mL/[min 1.73 m2]) confer an increased risk of overall and CV mortality during 7-year follow-up (35% for all-cause death and 42% for death from CV causes) [15]. Our data are in line with such results, especially when lower eGFR values are present; eGFR values b 30 mL/(min 1.73 m 2) identify a subgroup of patients at risk for adverse events at follow-up among patients with TTC. The ability of eGFR in identifying subjects at risk for adverse events at follow-up, beyond possible corrections for potential bias in multivariate analysis, is probably justified by the fact that eGFR includes variables usually considered in common multivariate analysis such as age, race, and sex, which may account for the efficacy of eGFR in stratifying the risk in subjects with TTC.
Table 2 Baseline features, and events during hospitalization and at follow-up stratified for eGFR nadir values during hospitalization for a TTC episode
Age Male Hypertension Dyslipidemia Obesity Smoker Diabetes Pulmonary disease Emotional stress Physical stress No stress Hospitalization days Adverse events at follow-up
eGFR: N60
eGFR: 60-30
eGFR: b30
P
P
P
(n = 45)
(n = 43)
(n = 20)
N60 vs 60-30
N60 vs b30
60-30 vs b30
66.91 ± 10.32 2% 64% 40% 27% 16% 20% 9% 40% 31% 29% 6.8 ± 2.6 13%
75.12 ± 8.20 5% 91% 35% 26% 14% 26% 29% 23% 49% 30% 8.2 ± 3.5 14%
81.50 ± 7.29 25% 85% 55% 15% 10% 45% 40% 10% 60% 30% 10.6 ± 3.6 40%
.001 .535 .002 .624 .909 .834 .537 .031 .093 .091 .891 .049 .933
.001 .002 .095 .268 .310 .556 .038 .004 .015 .028 .928 .001 .015
.004 .016 .510 .135 .355 .667 .127 .394 .218 .417 .985 .016 .020
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previously described cases of acute renal failure combined with digoxin toxicity and bradyarrhythmia as a possible trigger of TTC [25]. The role of renal dysfunction in the mechanism of TTC is still unclear but may probably represent a comorbidity such as malignancy, rheumatic disease, sepsis [26], pneumonia, and cerebrovascular diseases [27] that should be considered for risk stratification in patients with TTC. 4.3. Limitations
Fig. 3. Estimated GFR nadir values during hospitalization and incidence of adverse events at follow-up.
These are preliminary results to be confirmed in larger cohorts of patients. Further and more adequately powered prospective studies are warranted to clarify the assay standardization, the optimal cutoff, and the prognostic value of eGFR in association with other biomarkers and clinical scores. Contrast-induced nephropathy may have been related to the incidence of adverse events and hospital stay; however, because all subjects enrolled in the study underwent coronary angiography at admission and therefore contrast-induced nephropathy is impossible to distinguish from acute worsening of renal failure linked with TTC, the effect of contrast-induced nephropathy may be hypothesized but not exactly quantified. 5. Conclusions
The mechanisms by which renal impairment may be associated with a poorer outcome are not completely clear. Renal dysfunction could reflect a more generalized vascular disease and a wide range of comorbidities [16,17]. Furthermore, increased levels of biomarkers associated with both HF and diffuse serosal effusion could be present even in patient with TTC. Indeed, we found that CA-125, a tumor biomarker produced by mesothelial cells from the pleura, pericardium, and peritoneum, could be used as predictor of adverse events at follow-up with 80% of sensitivity and 76% of specificity [18].
4.2. Kidney dysfunction and TTC Higher levels of catecholamines, the main driver of TTC [19], have been found in end-stage renal disease. Elias et al [20] showed how elevated plasma concentrations of norepinephrine and dopamine were significantly elevated in patients with end-stage renal disease undergoing maintenance hemodialysis and slightly decreased by hemodyalisis [21]. More recently, Shin et al [22] described a case series of 7 patients with renal dysfunction who experienced a TTC episode. Three of these patients were on maintenance hemodialysis, and 4 patients had AKI. TTC has also been reported during peritoneal dialysis [23,24]. We have
Fig. 4. Kaplan-Meier curves showing adverse events at follow-up according to eGFR nadir values during hospitalization (log-rank P b .01).
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