Serum phosphate levels reflect responses to ... - Wiley Online Library

Journal of Arrhythmia 31 (2015) 38–42

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Original Article

Serum phosphate levels reflect responses to cardiac resynchronization therapy in chronic heart failure patients Yoshiyuki Kamiyama, MD, PhDa, Hitoshi Suzuki, MD, PhDa,b,n, Shinya Yamada, MD, PhDa, Takashi Kaneshiro, MD, PhDa, Yasuchika Takeishi, MD, PhDa,b a b

Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan Department of Arrhythmia and Cardiac Pacing, Fukushima Medical University, Fukushima, Japan

art ic l e i nf o

a b s t r a c t

Article history: Received 8 April 2014 Received in revised form 11 June 2014 Accepted 27 June 2014 Available online 20 August 2014

Background: Recent studies have shown that high levels of serum phosphate are associated with adverse cardiovascular events. However, little is known about the relation between phosphate levels and improvement of cardiac function in chronic heart failure (CHF) patients who underwent cardiac resynchronization therapy (CRT). The purpose of this study was to examine whether serum phosphate levels were able to predict responders to CRT and adverse cardiac events. Methods: The study population consisted of 30 CHF patients (24 males, mean age 65.778.5 years) who received CRT with defibrillator (CRT-D) implantation. Levels of serum phosphate were measured before, and 6 months after, CRT-D implantation. Left ventricular end-diastolic volume and end-systolic volume were assessed simultaneously by echocardiography. In addition, the rate of re-hospitalization due to worsening of heart failure was investigated. All patients were divided into 2 groups: responders (Group-R, n¼ 18) and nonresponders (Group-NR, n¼12) to CRT-D. Responders were defined as patients who showed 415% reduction in left ventricular end-systolic volume. We compared these parameters between the 2 groups. Results: Serum phosphate levels were significantly lower in Group-R than in Group-NR (3.370.2 vs. 3.770.4 mg/dL, p¼0.01). The rate of re-hospitalization was lower in Group-R than in Group-NR (0% vs. 33%, p¼0.018). Multivariate analysis showed that serum phosphate levels had a predictive power to determine responders to CRT (odds ratio 0.008, 95% confidence interval 0.000–0.348, p¼0.015). Conclusions: These results suggest that serum phosphate levels might predict both responders to CRT, and adverse cardiac events, in CHF patients with CRT-D. & 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.

Keywords: Cardiac resynchronization therapy Chronic heart failure Serum phosphate

1. Introduction In clinical practice, quantification of serum phosphate levels is useful for the diagnosis and management of various disorders including bone, parathyroid, and renal diseases [1]. In addition, recent studies have shown that high levels of serum phosphate, even within the normal range, may contribute to the increased risk of cardiovascular disease such as myocardial infarction and heart failure [2–4]. Interestingly, Ess et al. have reported that the association of serum phosphate concentrations with disease severity and long-term outcome in patients with chronic heart failure (CHF) is independent from concomitant renal dysfunction [4]. Their data suggest that management focused on serum phosphate levels might be important for patients with CHF.

n Correspondence to: Department of Arrhythmia and Cardiac Pacing, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. Tel.: þ 81 24 547 1190; fax: þ 81 24 548 1821. E-mail address: [email protected] (H. Suzuki).

Cardiac resynchronization therapy (CRT) is an effective treatment for drug-refractory severe heart failure with electro-mechanical delay. Previous studies have demonstrated that CRT improves clinical symptoms, exercise capacity, quality of life, and mortality in CHF [5–7]. However, responses to CRT have not been assured in all CHF patients, with about 30% of patients not responding to CRT [8]. Therefore, the aim of this study was to evaluate whether the serum phosphate levels before CRT implantation were able to predict responders to CRT, as well as adverse cardiac events. For this purpose, we examined the relation between serum phosphate levels and clinical, laboratory, and echocardiographic findings in CHF patients with CRT implantation.

2. Material and methods 2.1. Study population and protocol The study population consisted of 30 CHF patients (24 males, mean age 65.77 8.5 years) who had received successive CRT with

http://dx.doi.org/10.1016/j.joa.2014.06.006 1880-4276/& 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.

Y. Kamiyama et al. / Journal of Arrhythmia 31 (2015) 38–42

defibrillator (CRT-D) implantation at Fukushima Medical University Hospital, Fukushima, Japan. Eligibility criteria for CRT were New York Heart Association (NYHA) class III/IV symptoms of heart failure despite receiving optimal medical therapy, left ventricular ejection fraction (LVEF) of 35% or less on echocardiography, and a QRS duration of 120 ms or more. The exclusion criteria were acute coronary syndrome within 6 months, chronic obstructive pulmonary disease, and hemodialysis treatment. Clinical status was evaluated before CRT-D implantation. Assessments included history of hypertension, diabetes mellitus, ischemic etiology, atrial fibrillation, present medications such as beta-blockers, angiotensin converting enzyme inhibitors/angiotensin II receptor blockers, diuretics, spironolactones, statins, and amiodarone. Patients were followed-up in our hospital for 6 months after discharge, and extensively evaluated before, and 6 months after, CRT-D implantation. NYHA classification, QRS duration, laboratory data, and echocardiographic findings were assessed. In addition, adverse cardiac events (defined as re-hospitalization due to worsening of heart failure within 6 months after CRT-D implantation), were investigated. All patients were divided into 2 groups: responders to CRT-D (Group-R, n ¼18) and non-responders to CRT-D (GroupNR, n ¼12). Responders were defined as patients who showed 415% reduction in left ventricular end-systolic volume (LVESV). Written informed consent was obtained from all study subjects. The study protocol was approved by the Ethical Committee of Fukushima Medical University (approval number, 823; approval date, March 23, 2012).

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using a paired t-test. Categorical variables were analyzed by using a chi-square test. Multivariate logistic regression analysis was used to identify the predictors for CRT responders. The variables selected for multivariate analysis were those with po0.2 in the univariate models. All analyses were performed with SPSS for Windows, version 17.0 (SPSS Inc., Chicago, IL). A p value o0.05 was considered statistically significant.

3. Results Baseline characteristics of 30 patients are displayed in Table 1. The underlying etiologies of heart failure were ischemic in 23.3% of patients, and non-ischemic in 76.7% of patients. The non-ischemic etiology consisted of dilated cardiomyopathy in 78.3%, hypertensive heart disease in 8.7%, valvular heart disease in 8.7%, and hypertrophic cardiomyopathy in 4.3% of patients. Most of the patients received optimal medical treatment. Serum phosphate level was significantly lower in Group-R than in Group-NR (3.370.2 vs. 3.7 70.4 mg/dL, p ¼0.01). Except for the serum phosphate level, there were no differences in basic characteristics between the 2 groups (Table 2). Table 3 shows the changes in clinical and functional parameters before and 6 months after CRT-D implantation. NYHA classification as well as serum level of BNP improved in Group-R (NYHA: 3.170.5 to 2.470.5, po0.001; BNP: 437.2 (589.5) to 137.5 (250.8) pg/mL, p¼0.01). In addition, LVEDV, LVESV, and LVEF improved in

2.2. Blood sample analysis Blood samples were collected from all patients before CRT-D implantation, in stable states of heart failure, and at 6 months after CRT-D implantation. We measured levels of serum phosphate, serum creatinine, serum calcium, high-sensitivity C-reactive protein (hs-CRP), hemoglobin, and brain natriuretic peptide (BNP). Estimated glomerular filtration rate (eGFR) was calculated by using the Modification of Diet in Renal Disease equation in keeping with the criteria of the 2002 Kidney Disease Outcome Quality Initiative guidelines [9]. 2.3. Echocardiographic analysis Transthoracic echocardiography was performed at baseline and 6 months after CRT-D implantation. Left ventricular end-diastolic volume (LVEDV), LVESV, and LVEF were assessed by the modified biplane Simpson's methods. 2.4. CRT-D implantation CRT-D implantation was performed during compensated heart failure. The left ventricular lead was inserted through the coronary sinus with the help of a guiding catheter, and implanted at the lateral or postero-lateral vein. The right ventricular lead was positioned in the apex or septal of the right ventricular wall. All leads were inserted transvenously via the subclavian or cephalic vein route. The atrio-ventricular and inter-ventricular pacing delay was optimized by echocardiography to obtain the longest filling time or symmetrical wall motion after CRT-D implantation. 2.5. Statistical analysis Data are reported as means7SD, and skewed data are presented as median (inter-quartile range). Comparisons between Group-R and Group-NR were performed by using a Mann–Whitney U test. Data before and at 6 months after CRT-D implantation were compared by

Table 1 Baseline characteristics of study subjects. Age (years) Male (%) Height (cm) Body weight (kg) BMI (kg/m2) NYHA Medical history Hypertension (%) Diabetes (%) Hyperuricemia (%) Ischemic (%) Atrial fibrillation (%) Medication β-blocker (%) ACEI/ARB (%) Diuretic (%) Spironolactone (%) Statin (%) Amiodarone (%) Blood examination eGFR (mL/min/1.73 m2) Phosphate (mg/dL) Calcium (mg/dL) Hs-CRP (mg/dL) Hemoglobin (g/dL) BNP (pg/mL) ECG QRS duration (ms) Echocardiography LVEDV (mL) LVESV (mL) LVEF (%)

65.7 7 8.5 24 (80.0%) 160.2 7 8.9 58.9 7 11.5 22.8 7 3.8 3.2 7 0.6 11 (36.7%) 9 (30.0%) 9 (30.0%) 7 (23.3%) 4 (13.3%) 30 (100%) 26 (86.7%) 28 (93.3%) 15 (50.0%) 15 (50.0%) 17 (56.7%) 53.0 7 17.1 3.5 7 0.3 9.1 70.50 0.09 (0.11) 12.8 7 2.1 287.0 (418.0) 159.4 7 28.7 174.4 7 71.4 124.27 60.0 28.3 7 8.4

BMI, body mass index; NYHA, New York Heart Association; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; Hs-CRP, high-sensitivity C-reactive protein; BNP, brain natriuretic peptide; ECG, electrocardiography; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction.


Group-R (LVEDV: 183.9768.4 to 124.3732.9 mL, p¼ 0.001; LVESV: 137.5757.5 to 79.0728.1 mL, po0.001; LVEF: 26.378.6 to 37.4710.8%, po0.001). However, such improvements were not

Table 2 Baseline characteristic of responders and non-responders to cardiac resynchronization therapy.

Age (years) Male (%) Height (cm) Body weight (kg) BMI NYHA Medical history Hypertension (%) Diabetes (%) Hyperuricemia (%) Ischemic (%) Atrial fibrillation (%) Medication β-blocker (%) ACEI/ARB (%) Diuretic (%) Spironolactone (%) Statin (%) Amiodarone (%) Blood examination eGFR (mL/min/ 1.73 m2) Phosphate (mg/dL) Calcium (mg/dL) Hs-CRP (mg/dL) Hemoglobin (g/dL) BNP (pg/mL) ECG QRS duration (ms) Echocardiography LVEDV (mL) LVESV (mL) LVEF (%)

Responders (n ¼18)

Non-responders (n¼ 12)

p Value

65.5 79.7 16 (88.9%) 160.8 7 9.5 61.17 12.5 23.5 74.4 3.17 0.5

65.9 7 6.9 8 (66.7%) 159.3 7 8.2 55.6 7 9.3 21.8 72.4 3.3 7 0.7

0.90 0.15 0.65 0.20 0.22 0.21

6 4 6 3 2

5 5 3 4 2

0.77 0.27 0.64 0.30 0.66

(33.3%) (28.6%) (33.3%) (16.7%) (11.1%)

(38.9%) (31.3%) (25.0%) (33.3%) (16.7%)

18 (100%) 16 (88.9%) 17 (94.4%) 8 (44.4%) 9 (50.0%) 10 (55.6%)

12 (100%) 10 (83.3%) 11 (91.7%) 7 (58.3%) 6 (50.0%) 7 (58.3%)

54.0 715.6

51.5 7 19.8

0.71

3.3 70.2 9.17 0.5 0.09 (0.13) 13.0 7 2.2 437.2 (589.5)

3.7 7 0.4 9.2 7 0.6 0.90 (0.07) 12.5 7 2.0 275.6 (155)

0.01 0.75 0.50 0.55 0.21

164.3 729.0

152.2 7 27.6

0.26

183.9 7 68.4 137.5 7 57.7 26.3 78.6

159.3 7 80.2 111.0 7 65.8 31.4 77.6

0.38 0.26 0.11

0.66 0.78 0.47

observed in Group-NR. The serum phosphate level significantly increased in Group-NR (3.770.4 to 3.970.3 mg/dL, p¼0.042), but not in Group-R (3.370.2 to 3.270.3 mg/dL, NS). The occurrence of re-hospitalization within 6 months after CRT-D implantation was lower in Group-R than in Group-NR (0% vs. 33%, p¼ 0.018) as shown in Fig. 1. Multivariate analysis showed that serum phosphate was able to predict responders to CRT (odds ratio 0.008, 95% confidence interval 0.000–0.348, p ¼0.015), as shown in Table 4.

4. Discussion The present study demonstrated that changes in serum phosphate levels were related to responses to CRT, and were also associated with an increased risk of adverse cardiac events. CRT has been proven to be effective in improving clinical symptoms, exercise capacity, quality of life, and mortality in CHF patients with impaired left ventricular systolic function and intraventricular conduction delay [5–7]. However, such responses to CRT have not been recognized in all CRT candidates, with 30% of patients not responding to CRT [8]. Therefore, various clinical studies have attempted to identify parameters

100 0.55


The rate of re-hospitalization (%)

40

p = 0.018

90 80 70 60 50 40

33%

30 20 10 0

0% Responders

Non-Responders

Fig. 1. The rate of re-hospitalization due to worsening of heart failure within 6 months after cardiac resynchronization therapy with defibrillator implantation. The occurrence of re-hospitalization was lower in Group-R than in Group-NR (0% vs. 33%, p ¼0.018).

Table 3 Change in clinical and functional parameters before and 6 months after cardiac resynchronization therapy with defibrillator implantation. Responders (n¼ 18)

NYHA Blood examination eGFR (mL/min/1.73 m2) Phosphate (mg/dL) Calcium (mg/dL) Hs-CRP (mg/dL) Hemoglobin (g/dL) BNP (pg/mL) ECG QRS duration (ms) Echocardiography LVEDV (mL) LVESV (mL) LVEF (%)

Non-responders (n¼ 12)

Baseline

6 months

p Value

Baseline

6 months

p Value

3.17 0.5

2.4 70.5

o0.001

3.3 70.7

3.0 7 0.4

0.10

54.0 715.6 3.3 70.2 9.17 0.5 0.09 (0.13) 13.0 7 2.2 437.2 (589.5)

50.5 715.0 3.2 70.3 9.2 70.5 0.10 (0.19) 12.5 7 1.7 137.5 (250.8)

0.18 0.32 0.32 0.81 0.11 0.01

51.5 719.8 3.7 70.4 9.2 70.6 0.90 (0.07) 12.5 7 2.0 275.6 (155)

45.4 7 18.2 3.9 7 0.3 9.0 7 0.5 0.06 (0.15) 11.8 7 1.2 235.0 (423.3)

0.26 0.042 0.43 0.22 0.30 0.77

164.37 29.0

148.2 718.7

0.06

152.2 7 27.6

137.3 718.9

0.09

183.9 7 68.4 137.5 7 57.5 26.3 78.6

124.3732.9 79.0 728.1 37.4 7 10.8

0.001 o0.001 o0.001

159.3 7 80.2 111.0 765.8 31.4 7 7.6

156.17 68.0 105.2 7 53.1 33.97 6.4

0.85 0.61 0.10



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Table 4 Univariate and multivariate logistic regression analysis of predictors of responders. Univariable

Age (years) Sex (male) NYHA Atrial fibrillation eGFR (mL/min/1.73 m2) Phosphate (mg/dL) Calcium (mg/dL) Hs-CRP (mg/dL) Hemoglobin (g/dL) BNP (pg/mL) QRS duration (ms) LVEDV (mL) LVESV (mL) LVEF (%)

Multivariable

OR (95% CI)

p

0.994 0.250 0.478 0.600 1.009 0.004 0.782 2.083 1.120 1.002 1.016 1.005 1.008 0.920

0.89 0.15 0.31 0.57 0.70 0.008 0.74 0.53 0.54 0.22 0.26 0.38 0.26 0.12

(0.911–1.985) (0.037–1.668) (0.117–1.961) (0.990–3.634) (0.965–1.054) (0.000–0.234) (0.180–3.398) (0.206–21.084) (0.784–1.600) (0.999–1.004) (0.988–1.045) (0.994–1.017) (0.994–1.023) (0.828–1.023)

OR (95% CI)

p

0.311 (0.017–5.785)

0.43

0.008 (0.000–0.348)

0.015

0.935 (0.824–1.061)

0.30

OR, odds ratio; CI, confidence interval; BMI, body mass index; NYHA, New York Heart Association; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; Hs-CRP, high-sensitivity C-reactive protein; BNP, brain natriuretic peptide; ECG, electrocardiography; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction.

that might predict a response to CRT using either selection criteria [10–13]. These include not only the QRS duration and cardiac dyssynchronous parameters assessed by the echocardiography, but also biomarkers such as BNP, eGFR, and hs-CRP. Our present study demonstrated for the first time that serum phosphate levels might predict responders to CRT, as well as patients who experience adverse cardiac events, in CHF patients treated with CRT-D. Phosphorus is essential for organic activity such as cellular signal transduction, membrane transport, mineral metabolism, and energy exchange [1]. Bone and teeth store 80% of the total body phosphorus. Intracellular phosphorus consists of the form of organic compounds such as adenosine triphosphate, and free anions like H2PO4 that are referred to as phosphate. Serum phosphorus primarily occurs in the form of inorganic phosphate, which is maintained at a normal range by the regulation of dietary absorption, bone formation, and renal excretion, as well as equilibration with intracellular stores. The most common reason for hyperphosphatemia is inadequate glomerular function in patients with chronic kidney disease [14]. In patients with chronic kidney disease, higher serum phosphate levels are associated with increased risk of cardiovascular diseases [3]. In addition, higher serum phosphate levels, even within normal range, have been associated with a higher risk of cardiovascular disease in patients with prior myocardial infarction [2]. Serum phosphate levels promote vascular injury directly, and are associated with vascular smooth muscle cell calcification, which may increase vascular stiffness and contribute to disease progression. Additionally, higher levels of phosphate are involved in heart failure progression through their interaction with vitamin D, parathyroid hormone, and fibroblast growth factor 23, and also represent a marker of low vitamin D levels [15]. Parathyroid hormone and vitamin D have been linked to heart failure, and are significantly associated with all causes and cardiovascular mortality in CHF patients. In the present study, we could not measure the various factors involved in the metabolism of phosphorus. Larger studies are needed to identify the mechanism by which serum phosphate levels could function as a predictor of responders to CRT, and predicting adverse cardiac events, in patients with CRT-D implantation. The limitations of the present study were that it had a short follow-up period and a small number of patients. Thus, a study with a longer follow-up period and a larger patient population is needed in the future.

5. Conclusions In summary, serum phosphate levels might be a predictor of patients who respond well to CRT, and those who experience adverse cardiac events, after CRT-D implantation, providing a new insight into the decision-making process and management for CRT-D implantation in patients with severe CHF.

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