J Nephrol DOI 10.1007/s40620-014-0075-y
ORIGINAL ARTICLE
Calcium, phosphate and calcium phosphate product are markers of outcome in patients with chronic heart failure Richard M. Cubbon • Ceri Haf Thomas • Michael Drozd • John Gierula • Haqeel A. Jamil • Rowenna Byrom • Julian H. Barth • Mark T. Kearney • Klaus K. A. Witte
Received: 19 October 2013 / Accepted: 21 February 2014 Ó Italian Society of Nephrology 2014
Abstract Background Serum calcium (Ca) and inorganic phosphate (Pi) concentrations and calcium-phosphate product (CPP) levels are positively associated with worse outcomes in patients with chronic kidney disease, but there are few data for Pi or Ca and none for CPP in patients with chronic heart failure (CHF). Methods Unselected, consecutive patients with CHF (left ventricular ejection fraction, LVEF B45 %) were enrolled in a prospective observational study for the occurrence of hospitalisation and mortality. Blood samples were collected at the time of recruitment and analysed immediately. Results Patients (n = 713) were on contemporary optimal treatment and mean (standard error, SE) follow-up was 765 (18.9) days. Mean (SE) Ca was 2.29 (0.004) mmol/l. Median (interquartile range, IQR) Pi was 1.11 (0.98–1.23) mmol/l and median CPP 2.53 (2.21–2.88) mmol2/l2. LVEF correlated inversely with Ca, natural log-transformed (Ln)Pi, and LnCPP. There was no difference in CPP between classes of symptom severity or diabetes status. Ca and LnCPP (but not LnPi) were associated with total mortality. Ca was significantly associated with progressive HF and non-cardiovascular death but not with sudden
R. M. Cubbon C. H. Thomas M. Drozd J. Gierula H. A. Jamil R. Byrom M. T. Kearney K. K. A. Witte (&) Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Clarendon Way, Leeds LS2 9JT, UK e-mail: [email protected] J. H. Barth Department of Clinical Biochemistry, Leeds Teaching Hospitals NHS Trust, Leeds, UK
death. Binary logistic regression analyses showed that LnPi and LnCPP were associated with risk of hospitalisation. Conclusions Ca, Pi and CPP could be useful additional variables in determining risk in CHF patients. Further work is required to elucidate the mechanisms underlying the adverse influence and determine whether lowering phosphate levels per se in CHF patients is of benefit. Keywords failure
Left ventricular dysfunction Calcium Heart
Introduction Serum calcium (Ca) and inorganic phosphate (Pi) concentrations and calcium-phosphate product (CPP) levels are positively associated with worse outcomes in patients with chronic kidney disease (CKD) [1–3] and although patients with chronic heart failure (CHF) share aetiological factors and co-morbidities and experience similar high levels of cardiovascular (CV) and non-cardiovascular (nonCV) mortality there are few data for Pi [4, 5] or calcium [6] and none for the CPP describing whether these measures of mineral balance are related to important outcomes including hospitalisation in CHF patients. Phosphate and calcium share regulatory factors including parathyroid hormone (PTH), 1,25-(OH)2 vitamin D, and fibroblast growth factor-23 (FGF-23), all of which are associated with mortality and disease progression in CHF patients [5–9]. On the other hand, CPP, potentially a better indicator of overall calcium-phosphate homeostasis [10, 11], has never been included in CHF outcome analyses. If calcium, Pi or calcium phosphate product are related to hospitalisation or mortality in clinical practice, not only is it possible that they could contribute to improved risk
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stratification models to help focus services to those CHF patients at highest risk, but manipulating their levels might improve outcomes. Hence the aim of the present analysis was to use prospectively collected data from a large cohort study of consecutive patients attending a specialist heart failure clinic with a diagnosis of CHF due to left ventricular systolic dysfunction (LVSD) to define the associations between serum Pi, calcium, CPP and important outcomes.
Table 1 Patient characteristics Patients (n = 713) Age (years)
70 (0.4)
Male sex, % (n)
72 (512)
NYHA class, % (n) I
18 (130)
II
50 (353)
III
31 (220)
IV
Methods Between June 2006 and December 2011, 1091 unselected, consecutive patients with CHF due to LVSD (LV ejection fraction B45 % on transthoracic echocardiography using Simpson’s biplane method [12]) attending four UK hospital outpatient cardiology clinics were enrolled and prospectively observed for the occurrence of hospitalisation and mortality as previously described [13]. Along with an echocardiogram performed by sonographers blinded to patient characteristics, all patients received a resting 12-lead electrocardiograph, posteroanterior chest radiograph (patient characteristics blinded) and venous blood sample collected at rest. CHF severity was defined by New York Heart Association (NYHA) class and glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease calculation [14]. The presence or absence of diabetes and ischaemic heart disease (IHD) was established at recruitment using detailed medical history and available investigations. Blood samples were collected at the time of recruitment and analysed immediately. International system (SI) units were converted to conventional units (mg/dl) by multiplying by 0.25 for calcium and 0.323 for phosphate. Laboratory normal ranges were 0.8–1.4 mmol/l for serum Pi, and 2.2–2.6 mmol/l for serum Ca. Serum Ca was corrected for albumin level. CPP was calculated as the product of calcium and phosphate (Ca2? 9 PO4). Outcome measures included all-cause mortality, mode-specific mortality, and hospitalisation. Data on mortality were collected via the UK Office of Population, Censuses and Surveys (i.e. data were available for all recruited patients). Mode of death was established by two senior physicians, and classified as either CV or non-CV and further sub-defined as: (1) progressive heart failure (HF) if occurring after a documented period of symptomatic or haemodynamic deterioration; (2) sudden death, if occurring within 1 h of symptomatic change, or whilst unobserved; and (3) non-CV, if neither of the above applied, and other cardiovascular causes (e.g. stroke and myocardial infarction) were excluded [15]. Heart failure hospitalisation was assessed as a binary
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1 (10)
LV ejection fraction (%)
32.1 (0.3)
eGFR (ml/min/1.73 m2)
54.3 (0.7)
Ischaemic aetiology, % (n) Diabetes, % (n) ACEi/ARB prescription, % (n) Beta-blocker prescription, % (n)
62 (443) 27 (196) 86.9 (618) 82 (583)
MRA antagonist prescription, % (n)
42.9 (305)
Cardiac resynchronisation therapy, % (n)
32.4 (231)
NYHA class New York Heart Association class, LV left ventricular, eGFR estimated glomerular filtration rate, ACEi angiotensin converting enzyme inhibitor, ARB aldosterone receptor blocker, MRA mineralocorticoid receptor antagonist
outcome (yes/no) during the first year of follow-up after inclusion, and defined as an acute onset or worsening of signs and symptoms of HF requiring at least 24 h of overnight hospitalisation and treatment with intravenous diuretics. Skewness tests were used to test for normality (defined as -1 to 1), and non-normally distributed data were natural-log transformed to achieve normality when used in regression analyses. Categorical data are presented as percentage (number), normally distributed data as mean and standard error of mean (SEM), and non-normally distributed data as median and interquartile range (IQR). Analyses were conducted using PASW statistics version 18 (SPSS Inc., Chicago, IL, USA). Cox regression univariable and multivariate analyses were used to explore influences on mortality. Based upon our previous work [14], we included sex, age, eGFR, diabetes, NYHA class, IHD, and loop diuretic dose in the multivariate analysis in addition to calcium, Pi and log transformed CPP. Binary logistic regression analysis was used in the analysis of hospitalisation and the Kruskal–Wallis test to look at differences in variables across NYHA classes. Partial residual plots with lines of best fit were also performed for all variables used in Cox regression analyses and revealed no deviation from the assumption of proportional hazards. Statistical significance was defined as p \ 0.05. All patients provided written informed consent and ethics approval was given by the Leeds West Research Ethics Committee.
J Nephrol Table 2 Hazard ratios (HR) and 95 % confidence intervals (CI) of univariate Cox-regression analyses with calcium, phosphate and CPP HR (95 % CI) All-cause mortality
OR (95 % CI) Mode-specific mortality Progressive HF
LnPi (mmol/l)
1.94 (0.95–3.97)
Calcium (mmol/l)
8.20 (2.20–30.53)*
2 2
LnCPP (mmol /l )
2.27 (1.14–4.51)*
2.38 (0.70–8.03) 19.34 (2.46–151.84)* 3.03 (0.94–9.71)
Hospitalisation Sudden death 2.69 (0.52–13.87) 5.94 (0.26–136.68) 3.01 (0.62–14.62)
Non-CV 1.72 (0.53–5.56) 17.45 (2.84–127.56)* 2.24 (0.73–6.92)
17.00 (4.04–71.55)* 2.32 (0.13–40.82) 15.43 (3.85–61.84)*
CPP calcium-phosphate product, OR odds ratio, LnPi natural logarithm of inorganic phosphate, LnCPP natural logarithm of calcium-phosphate product, CV cardiovascular * Statistical significance (p \ 0.05)
Results The present results concern those patients with a full dataset including calcium and Pi recorded at the time of enrolment (n = 713) (Table 1). Patients were on contemporary optimal treatment and mean follow-up was 765 days (SEM 18.5). Skewness testing showed that Pi and CPP were not normally distributed, therefore they were natural log-transformed (LnPi and LnCPP) when included in regression analyses. Calcium was normally distributed with a mean of 2.29 (0.004) mmol/l. Median Pi was 1.11 (0.98–1.23) mmol/l and median CPP was 2.53 (2.21–2.88) mmol2/l2. Only 71 patients had Pi levels above the normal range, 7 had high calcium levels and 7 had high CPP. Markers of severity LV ejection fraction correlated inversely with calcium (Pearson coefficient -0.109; p = 0.004), LnPi (Pearson coefficient -0.107; p = 0.005), and LnCPP (Pearson coefficient -0.125; p \ 0.001). As expected, calcium, LnPi, and LnCPP all correlated with eGFR. There was no difference in CPP between classes of symptom severity defined by NYHA class (p = 0.53), or according to diabetes status.
interval (CI) 1.3–5.6, p = 0.007]. These findings were also unchanged when the cohort was stratified by eGFR (according to groups with eGFR below 30, between 30 and 60, or above 60 ml/kg/1.73 m2). Table 2 also shows mode-specific mortality. Calcium was significantly associated with both progressive HF and non-CV death (p = 0.005, for both), but not with sudden death. For every 1 mmol/l increase in calcium the risk of progressive HF death increased 19.3 fold, and the risk of non-CV death increased 17.4 fold. LnPi and LnCPP were not associated with risk of progressive HF death, sudden death or non-CV death. Hospitalisation and symptomatic status Heart failure related hospitalisation occurred in 43 individuals. Binary logistic regression analyses showed that both LnPi and LnCPP were significantly associated with risk of hospitalisation (Table 2). For every 2.72-fold increase in serum phosphate the risk of hospitalisation increased 8.9 fold and for every 2.72-fold increase in CPP the risk of hospitalisation increased 6.9 fold. Calcium was not significantly associated with hospitalisation. Multivariate analyses for hospitalisation were not conducted due to the small number of events.
Mortality outcomes Discussion A total of 157 deaths occurred over a follow-up period of 765 (18.9) days. On Cox regression analyses (Table 2), both calcium and LnCPP were significantly associated with total mortality, although this was not the case for LnPi. Every 1 mmol/l increase in calcium was associated with an 8.2-fold increase in risk and every 2.72-fold increase in CPP was associated with a 2.27-fold increase in risk. The association between LnCPP and risk of death persisted following adjustment for factors included in the multivariate analysis, shown in Fig. 1. In a multivariable Cox regression excluding eGFR, the hazard ratio for LnCPP was similar [2.7, 95 % confidence
Our data demonstrate that although most patients did not have abnormal levels, serum inorganic phosphate, calcium and CPP are positively associated with important outcomes in optimally treated heart failure patients independent of traditional risk factors such as renal dysfunction, diabetes mellitus and ischaemic aetiology. This adverse relationship of calcium and CPP with mortality in CHF has never been described before. Although there was no association between inorganic phosphate and mortality in our cohort, our novel demonstration of a significant relationship to hospitalisation is important since this outcome is a major
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LnCPP (mmol 2/L2)
HR (95% CI HR)
p value
3.31 (1.56-7.02)
0.002
Male sex
1.76 (1.18-2.61)
0.005
Age (years)
1.06 (1.04-1.08)
0.000
0.999 (0.988-1.009)
0.798
1.60 (1.16-2.30)
0.005
eGFR (mL/min/1.73 m2) Diabetes NYHA class I
0.000
NYHA class II (vs. I)
1.25 (0.67-2.31)
NYHA class III (vs. I)
2.21 (1.19-4.11)
NYHA class IV (vs. I)
5.59 (2.20-14.23)
Ischaemic aetiology
1.58 (1.03-2.41)
0.035
Loop diuretic use
1.55 (0.97-2.47)
0.069
Fig. 1 Cox multivariate regression analysis of all-cause mortality with Forest plots of hazard ratios (HR) and 95 % confidence intervals (CI) of HR. LnCPP natural logarithm of calcium-phosphate product, eGFR estimated glomerular filtration rate, NYHA New York Heart Association
driver of the cost of heart failure treatment [16] and strongly related to the quality of life of patients with CHF [17]. In recent years much attention has been focused on vitamin D and PTH and their influence on outcomes in patients with and without established cardiovascular disease, particularly heart failure. On the other hand little attention has been given to the biochemical consequences of abnormalities of the vitamin D–parathyroid hormone axis and the hyperphosphataemic consequences of modest renal dysfunction. Elevated Pi and CPP levels are associated with vascular calcification [18, 19], and subclinical atherosclerosis [20], and are generally, although not universally [21], accepted as powerful predictors of cardiovascular mortality in patients on haemodialysis [1, 2, 22] peritoneal dialysis [3] and renal transplant recipients [23, 24] whereas, as with our data, calcium alone is not consistently associated with cardiovascular outcomes. Hence calcium and Pi control are priorities in the management of patients with renal dysfunction [25] and agents to control Pi levels that avoid calcium loading are increasingly prescribed [26, 27]. The data for both Pi and calcium in patients with CHF are much less advanced. Serum Pi seems to be associated with incident heart failure in patients with [28] and without existing cardiovascular disease [29], and calcium levels are related to mortality in patients without cardiovascular disease although individuals with both low and high levels are at increased risk [30]. Behind these data, little is known about whether calcium and Pi levels are independently
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related to outcome in patients with CHF or are merely confounders as a result of the highly prevalent renal impairment seen in CHF patients [31]. The data on Pi, for example, have to date revealed somewhat divergent results [4–6]. In 99 patients with heart failure, higher Pi levels were associated with heart failure hospitalisation, but not mortality [5], whereas in a retrospective analysis of 974 CHF patients combined mortality and cardiac transplantation did seem to be related to Pi levels, although calcium was not [4]. Mortality rates in this study were similar to those in our cohort, but almost 8 % reached the composite outcome by means of heart transplantation, which, as a physician driven event, is a potential source of bias. In contrast to these two studies, Zitterman et al. [6] could find no association between Pi or calcium and adverse outcomes including death, mechanical circulatory support, and heart transplantation over 90 days of follow-up in patients with severe heart failure. Mechanism of adverse effect High levels of Pi may promote vascular injury by deposition of hydroxyapatite crystals in soft tissues initiating an inflammatory response [32], vascular smooth muscle calcification [11], proliferation and conversion of smooth muscle cells to a fibroblastic or osteoblastic phenotype [33], all of which increase vascular resistance [20, 34]. However Pi also contributes to myocardial calcification [20, 31], inhibits 1,25-dihydroxyvitamin D3 synthesis (as part of vitamin D metabolism), impairs cardiac
J Nephrol
contractility [26, 35], and increases levels of PTH [32, 36, 37] and FGF-23 levels. This latter agent, which is upregulated by phosphate levels, is linked to left ventricular hypertrophy, and since it is associated with incident heart failure in patients with CKD [38], it might also be related to outcome in patients with CHF [7]. The importance of Pi and calcium in cardiac energetics via intracellular oxidative phosphorylation also suggests a possible mechanistic role of these minerals in the downstream performance and contractility of the heart [25, 39, 40].
Conclusions
Clinical relevance
Acknowledgments The work in the MTK laboratory is supported by the British Heart Foundation, MTK holds a British Heart Foundation Chair of Cardiology, RMC is a British Heart Foundation Intermediate Research Fellow [FS/12/80/29821], KKW holds an NIHR Clinician Scientist Award [NIHR-CS-012-032].
Despite unclear mechanisms, the principal significance of our findings is the prognostic relevance of Pi, calcium and CPP which may have the potential to be used in CHF prognostication. The Seattle Heart Failure model, the primary tool for predicting prognosis in CHF patients, uses 30 variables but none related to Ca or Pi homeostasis [41]. Although our finding that calcium may be a better indicator for mortality risk, and Pi a better indicator of hospitalisation risk, might be the result of a limited sample size, each could be used as indicators of risk of specific CHF outcomes. However, since both outcomes are important in defining populations that may benefit from more intensive CHF management, it may be useful to focus on CPP as an overall prognostic marker of combined CHF outcome. Furthermore, it is possible that lowering Pi levels in patients with CHF could improve outcomes, although this might best be done with phosphate binders that do not contain calcium [42]. However, any intervention will impact upon the complex network of other potential confounders (PTH, FGF-23), making inference of causal pathways challenging.
Limitations The present data have several important limitations. Our data exhibited wide confidence intervals, implying the need for a larger sample (or more events) in a validation cohort to ensure that our conclusions are robust. Secondly, as is the case with previous studies we did not account for vitamin D status and PTH [32, 43, 44], or other potential confounders such as FGF-23 [5–9, 23, 31], ethnicity, and smoking status. We also acknowledge that, although our patients were recruited consecutively with blood testing performed at the clinic visit at which recruitment to our project took place, we did not have calcium and Pi data for all, potentially introducing some bias. Finally, an analysis of this type can never address causality, and the results must be interpreted appropriately.
Our data demonstrate that calcium, inorganic phosphate and CPP could be useful additional variables in determining risk in patients with chronic heart failure and thereby potentially aid in stratifying risk to allow a focusing of attention on those at higher risk. Further work is required to elucidate the mechanisms underlying the adverse influence of these agents and determine whether lowering phosphate levels per se in CHF patients is of benefit.
Conflict of interest KKW and MTK have received research funding from Medtronic UK. No other conflict of interest to declare.
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ORIGINAL ARTICLE
Calcium, phosphate and calcium phosphate product are markers of outcome in patients with chronic heart failure Richard M. Cubbon • Ceri Haf Thomas • Michael Drozd • John Gierula • Haqeel A. Jamil • Rowenna Byrom • Julian H. Barth • Mark T. Kearney • Klaus K. A. Witte
Received: 19 October 2013 / Accepted: 21 February 2014 Ó Italian Society of Nephrology 2014
Abstract Background Serum calcium (Ca) and inorganic phosphate (Pi) concentrations and calcium-phosphate product (CPP) levels are positively associated with worse outcomes in patients with chronic kidney disease, but there are few data for Pi or Ca and none for CPP in patients with chronic heart failure (CHF). Methods Unselected, consecutive patients with CHF (left ventricular ejection fraction, LVEF B45 %) were enrolled in a prospective observational study for the occurrence of hospitalisation and mortality. Blood samples were collected at the time of recruitment and analysed immediately. Results Patients (n = 713) were on contemporary optimal treatment and mean (standard error, SE) follow-up was 765 (18.9) days. Mean (SE) Ca was 2.29 (0.004) mmol/l. Median (interquartile range, IQR) Pi was 1.11 (0.98–1.23) mmol/l and median CPP 2.53 (2.21–2.88) mmol2/l2. LVEF correlated inversely with Ca, natural log-transformed (Ln)Pi, and LnCPP. There was no difference in CPP between classes of symptom severity or diabetes status. Ca and LnCPP (but not LnPi) were associated with total mortality. Ca was significantly associated with progressive HF and non-cardiovascular death but not with sudden
R. M. Cubbon C. H. Thomas M. Drozd J. Gierula H. A. Jamil R. Byrom M. T. Kearney K. K. A. Witte (&) Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Clarendon Way, Leeds LS2 9JT, UK e-mail: [email protected] J. H. Barth Department of Clinical Biochemistry, Leeds Teaching Hospitals NHS Trust, Leeds, UK
death. Binary logistic regression analyses showed that LnPi and LnCPP were associated with risk of hospitalisation. Conclusions Ca, Pi and CPP could be useful additional variables in determining risk in CHF patients. Further work is required to elucidate the mechanisms underlying the adverse influence and determine whether lowering phosphate levels per se in CHF patients is of benefit. Keywords failure
Left ventricular dysfunction Calcium Heart
Introduction Serum calcium (Ca) and inorganic phosphate (Pi) concentrations and calcium-phosphate product (CPP) levels are positively associated with worse outcomes in patients with chronic kidney disease (CKD) [1–3] and although patients with chronic heart failure (CHF) share aetiological factors and co-morbidities and experience similar high levels of cardiovascular (CV) and non-cardiovascular (nonCV) mortality there are few data for Pi [4, 5] or calcium [6] and none for the CPP describing whether these measures of mineral balance are related to important outcomes including hospitalisation in CHF patients. Phosphate and calcium share regulatory factors including parathyroid hormone (PTH), 1,25-(OH)2 vitamin D, and fibroblast growth factor-23 (FGF-23), all of which are associated with mortality and disease progression in CHF patients [5–9]. On the other hand, CPP, potentially a better indicator of overall calcium-phosphate homeostasis [10, 11], has never been included in CHF outcome analyses. If calcium, Pi or calcium phosphate product are related to hospitalisation or mortality in clinical practice, not only is it possible that they could contribute to improved risk
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stratification models to help focus services to those CHF patients at highest risk, but manipulating their levels might improve outcomes. Hence the aim of the present analysis was to use prospectively collected data from a large cohort study of consecutive patients attending a specialist heart failure clinic with a diagnosis of CHF due to left ventricular systolic dysfunction (LVSD) to define the associations between serum Pi, calcium, CPP and important outcomes.
Table 1 Patient characteristics Patients (n = 713) Age (years)
70 (0.4)
Male sex, % (n)
72 (512)
NYHA class, % (n) I
18 (130)
II
50 (353)
III
31 (220)
IV
Methods Between June 2006 and December 2011, 1091 unselected, consecutive patients with CHF due to LVSD (LV ejection fraction B45 % on transthoracic echocardiography using Simpson’s biplane method [12]) attending four UK hospital outpatient cardiology clinics were enrolled and prospectively observed for the occurrence of hospitalisation and mortality as previously described [13]. Along with an echocardiogram performed by sonographers blinded to patient characteristics, all patients received a resting 12-lead electrocardiograph, posteroanterior chest radiograph (patient characteristics blinded) and venous blood sample collected at rest. CHF severity was defined by New York Heart Association (NYHA) class and glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease calculation [14]. The presence or absence of diabetes and ischaemic heart disease (IHD) was established at recruitment using detailed medical history and available investigations. Blood samples were collected at the time of recruitment and analysed immediately. International system (SI) units were converted to conventional units (mg/dl) by multiplying by 0.25 for calcium and 0.323 for phosphate. Laboratory normal ranges were 0.8–1.4 mmol/l for serum Pi, and 2.2–2.6 mmol/l for serum Ca. Serum Ca was corrected for albumin level. CPP was calculated as the product of calcium and phosphate (Ca2? 9 PO4). Outcome measures included all-cause mortality, mode-specific mortality, and hospitalisation. Data on mortality were collected via the UK Office of Population, Censuses and Surveys (i.e. data were available for all recruited patients). Mode of death was established by two senior physicians, and classified as either CV or non-CV and further sub-defined as: (1) progressive heart failure (HF) if occurring after a documented period of symptomatic or haemodynamic deterioration; (2) sudden death, if occurring within 1 h of symptomatic change, or whilst unobserved; and (3) non-CV, if neither of the above applied, and other cardiovascular causes (e.g. stroke and myocardial infarction) were excluded [15]. Heart failure hospitalisation was assessed as a binary
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1 (10)
LV ejection fraction (%)
32.1 (0.3)
eGFR (ml/min/1.73 m2)
54.3 (0.7)
Ischaemic aetiology, % (n) Diabetes, % (n) ACEi/ARB prescription, % (n) Beta-blocker prescription, % (n)
62 (443) 27 (196) 86.9 (618) 82 (583)
MRA antagonist prescription, % (n)
42.9 (305)
Cardiac resynchronisation therapy, % (n)
32.4 (231)
NYHA class New York Heart Association class, LV left ventricular, eGFR estimated glomerular filtration rate, ACEi angiotensin converting enzyme inhibitor, ARB aldosterone receptor blocker, MRA mineralocorticoid receptor antagonist
outcome (yes/no) during the first year of follow-up after inclusion, and defined as an acute onset or worsening of signs and symptoms of HF requiring at least 24 h of overnight hospitalisation and treatment with intravenous diuretics. Skewness tests were used to test for normality (defined as -1 to 1), and non-normally distributed data were natural-log transformed to achieve normality when used in regression analyses. Categorical data are presented as percentage (number), normally distributed data as mean and standard error of mean (SEM), and non-normally distributed data as median and interquartile range (IQR). Analyses were conducted using PASW statistics version 18 (SPSS Inc., Chicago, IL, USA). Cox regression univariable and multivariate analyses were used to explore influences on mortality. Based upon our previous work [14], we included sex, age, eGFR, diabetes, NYHA class, IHD, and loop diuretic dose in the multivariate analysis in addition to calcium, Pi and log transformed CPP. Binary logistic regression analysis was used in the analysis of hospitalisation and the Kruskal–Wallis test to look at differences in variables across NYHA classes. Partial residual plots with lines of best fit were also performed for all variables used in Cox regression analyses and revealed no deviation from the assumption of proportional hazards. Statistical significance was defined as p \ 0.05. All patients provided written informed consent and ethics approval was given by the Leeds West Research Ethics Committee.
J Nephrol Table 2 Hazard ratios (HR) and 95 % confidence intervals (CI) of univariate Cox-regression analyses with calcium, phosphate and CPP HR (95 % CI) All-cause mortality
OR (95 % CI) Mode-specific mortality Progressive HF
LnPi (mmol/l)
1.94 (0.95–3.97)
Calcium (mmol/l)
8.20 (2.20–30.53)*
2 2
LnCPP (mmol /l )
2.27 (1.14–4.51)*
2.38 (0.70–8.03) 19.34 (2.46–151.84)* 3.03 (0.94–9.71)
Hospitalisation Sudden death 2.69 (0.52–13.87) 5.94 (0.26–136.68) 3.01 (0.62–14.62)
Non-CV 1.72 (0.53–5.56) 17.45 (2.84–127.56)* 2.24 (0.73–6.92)
17.00 (4.04–71.55)* 2.32 (0.13–40.82) 15.43 (3.85–61.84)*
CPP calcium-phosphate product, OR odds ratio, LnPi natural logarithm of inorganic phosphate, LnCPP natural logarithm of calcium-phosphate product, CV cardiovascular * Statistical significance (p \ 0.05)
Results The present results concern those patients with a full dataset including calcium and Pi recorded at the time of enrolment (n = 713) (Table 1). Patients were on contemporary optimal treatment and mean follow-up was 765 days (SEM 18.5). Skewness testing showed that Pi and CPP were not normally distributed, therefore they were natural log-transformed (LnPi and LnCPP) when included in regression analyses. Calcium was normally distributed with a mean of 2.29 (0.004) mmol/l. Median Pi was 1.11 (0.98–1.23) mmol/l and median CPP was 2.53 (2.21–2.88) mmol2/l2. Only 71 patients had Pi levels above the normal range, 7 had high calcium levels and 7 had high CPP. Markers of severity LV ejection fraction correlated inversely with calcium (Pearson coefficient -0.109; p = 0.004), LnPi (Pearson coefficient -0.107; p = 0.005), and LnCPP (Pearson coefficient -0.125; p \ 0.001). As expected, calcium, LnPi, and LnCPP all correlated with eGFR. There was no difference in CPP between classes of symptom severity defined by NYHA class (p = 0.53), or according to diabetes status.
interval (CI) 1.3–5.6, p = 0.007]. These findings were also unchanged when the cohort was stratified by eGFR (according to groups with eGFR below 30, between 30 and 60, or above 60 ml/kg/1.73 m2). Table 2 also shows mode-specific mortality. Calcium was significantly associated with both progressive HF and non-CV death (p = 0.005, for both), but not with sudden death. For every 1 mmol/l increase in calcium the risk of progressive HF death increased 19.3 fold, and the risk of non-CV death increased 17.4 fold. LnPi and LnCPP were not associated with risk of progressive HF death, sudden death or non-CV death. Hospitalisation and symptomatic status Heart failure related hospitalisation occurred in 43 individuals. Binary logistic regression analyses showed that both LnPi and LnCPP were significantly associated with risk of hospitalisation (Table 2). For every 2.72-fold increase in serum phosphate the risk of hospitalisation increased 8.9 fold and for every 2.72-fold increase in CPP the risk of hospitalisation increased 6.9 fold. Calcium was not significantly associated with hospitalisation. Multivariate analyses for hospitalisation were not conducted due to the small number of events.
Mortality outcomes Discussion A total of 157 deaths occurred over a follow-up period of 765 (18.9) days. On Cox regression analyses (Table 2), both calcium and LnCPP were significantly associated with total mortality, although this was not the case for LnPi. Every 1 mmol/l increase in calcium was associated with an 8.2-fold increase in risk and every 2.72-fold increase in CPP was associated with a 2.27-fold increase in risk. The association between LnCPP and risk of death persisted following adjustment for factors included in the multivariate analysis, shown in Fig. 1. In a multivariable Cox regression excluding eGFR, the hazard ratio for LnCPP was similar [2.7, 95 % confidence
Our data demonstrate that although most patients did not have abnormal levels, serum inorganic phosphate, calcium and CPP are positively associated with important outcomes in optimally treated heart failure patients independent of traditional risk factors such as renal dysfunction, diabetes mellitus and ischaemic aetiology. This adverse relationship of calcium and CPP with mortality in CHF has never been described before. Although there was no association between inorganic phosphate and mortality in our cohort, our novel demonstration of a significant relationship to hospitalisation is important since this outcome is a major
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LnCPP (mmol 2/L2)
HR (95% CI HR)
p value
3.31 (1.56-7.02)
0.002
Male sex
1.76 (1.18-2.61)
0.005
Age (years)
1.06 (1.04-1.08)
0.000
0.999 (0.988-1.009)
0.798
1.60 (1.16-2.30)
0.005
eGFR (mL/min/1.73 m2) Diabetes NYHA class I
0.000
NYHA class II (vs. I)
1.25 (0.67-2.31)
NYHA class III (vs. I)
2.21 (1.19-4.11)
NYHA class IV (vs. I)
5.59 (2.20-14.23)
Ischaemic aetiology
1.58 (1.03-2.41)
0.035
Loop diuretic use
1.55 (0.97-2.47)
0.069
Fig. 1 Cox multivariate regression analysis of all-cause mortality with Forest plots of hazard ratios (HR) and 95 % confidence intervals (CI) of HR. LnCPP natural logarithm of calcium-phosphate product, eGFR estimated glomerular filtration rate, NYHA New York Heart Association
driver of the cost of heart failure treatment [16] and strongly related to the quality of life of patients with CHF [17]. In recent years much attention has been focused on vitamin D and PTH and their influence on outcomes in patients with and without established cardiovascular disease, particularly heart failure. On the other hand little attention has been given to the biochemical consequences of abnormalities of the vitamin D–parathyroid hormone axis and the hyperphosphataemic consequences of modest renal dysfunction. Elevated Pi and CPP levels are associated with vascular calcification [18, 19], and subclinical atherosclerosis [20], and are generally, although not universally [21], accepted as powerful predictors of cardiovascular mortality in patients on haemodialysis [1, 2, 22] peritoneal dialysis [3] and renal transplant recipients [23, 24] whereas, as with our data, calcium alone is not consistently associated with cardiovascular outcomes. Hence calcium and Pi control are priorities in the management of patients with renal dysfunction [25] and agents to control Pi levels that avoid calcium loading are increasingly prescribed [26, 27]. The data for both Pi and calcium in patients with CHF are much less advanced. Serum Pi seems to be associated with incident heart failure in patients with [28] and without existing cardiovascular disease [29], and calcium levels are related to mortality in patients without cardiovascular disease although individuals with both low and high levels are at increased risk [30]. Behind these data, little is known about whether calcium and Pi levels are independently
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related to outcome in patients with CHF or are merely confounders as a result of the highly prevalent renal impairment seen in CHF patients [31]. The data on Pi, for example, have to date revealed somewhat divergent results [4–6]. In 99 patients with heart failure, higher Pi levels were associated with heart failure hospitalisation, but not mortality [5], whereas in a retrospective analysis of 974 CHF patients combined mortality and cardiac transplantation did seem to be related to Pi levels, although calcium was not [4]. Mortality rates in this study were similar to those in our cohort, but almost 8 % reached the composite outcome by means of heart transplantation, which, as a physician driven event, is a potential source of bias. In contrast to these two studies, Zitterman et al. [6] could find no association between Pi or calcium and adverse outcomes including death, mechanical circulatory support, and heart transplantation over 90 days of follow-up in patients with severe heart failure. Mechanism of adverse effect High levels of Pi may promote vascular injury by deposition of hydroxyapatite crystals in soft tissues initiating an inflammatory response [32], vascular smooth muscle calcification [11], proliferation and conversion of smooth muscle cells to a fibroblastic or osteoblastic phenotype [33], all of which increase vascular resistance [20, 34]. However Pi also contributes to myocardial calcification [20, 31], inhibits 1,25-dihydroxyvitamin D3 synthesis (as part of vitamin D metabolism), impairs cardiac
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contractility [26, 35], and increases levels of PTH [32, 36, 37] and FGF-23 levels. This latter agent, which is upregulated by phosphate levels, is linked to left ventricular hypertrophy, and since it is associated with incident heart failure in patients with CKD [38], it might also be related to outcome in patients with CHF [7]. The importance of Pi and calcium in cardiac energetics via intracellular oxidative phosphorylation also suggests a possible mechanistic role of these minerals in the downstream performance and contractility of the heart [25, 39, 40].
Conclusions
Clinical relevance
Acknowledgments The work in the MTK laboratory is supported by the British Heart Foundation, MTK holds a British Heart Foundation Chair of Cardiology, RMC is a British Heart Foundation Intermediate Research Fellow [FS/12/80/29821], KKW holds an NIHR Clinician Scientist Award [NIHR-CS-012-032].
Despite unclear mechanisms, the principal significance of our findings is the prognostic relevance of Pi, calcium and CPP which may have the potential to be used in CHF prognostication. The Seattle Heart Failure model, the primary tool for predicting prognosis in CHF patients, uses 30 variables but none related to Ca or Pi homeostasis [41]. Although our finding that calcium may be a better indicator for mortality risk, and Pi a better indicator of hospitalisation risk, might be the result of a limited sample size, each could be used as indicators of risk of specific CHF outcomes. However, since both outcomes are important in defining populations that may benefit from more intensive CHF management, it may be useful to focus on CPP as an overall prognostic marker of combined CHF outcome. Furthermore, it is possible that lowering Pi levels in patients with CHF could improve outcomes, although this might best be done with phosphate binders that do not contain calcium [42]. However, any intervention will impact upon the complex network of other potential confounders (PTH, FGF-23), making inference of causal pathways challenging.
Limitations The present data have several important limitations. Our data exhibited wide confidence intervals, implying the need for a larger sample (or more events) in a validation cohort to ensure that our conclusions are robust. Secondly, as is the case with previous studies we did not account for vitamin D status and PTH [32, 43, 44], or other potential confounders such as FGF-23 [5–9, 23, 31], ethnicity, and smoking status. We also acknowledge that, although our patients were recruited consecutively with blood testing performed at the clinic visit at which recruitment to our project took place, we did not have calcium and Pi data for all, potentially introducing some bias. Finally, an analysis of this type can never address causality, and the results must be interpreted appropriately.
Our data demonstrate that calcium, inorganic phosphate and CPP could be useful additional variables in determining risk in patients with chronic heart failure and thereby potentially aid in stratifying risk to allow a focusing of attention on those at higher risk. Further work is required to elucidate the mechanisms underlying the adverse influence of these agents and determine whether lowering phosphate levels per se in CHF patients is of benefit.
Conflict of interest KKW and MTK have received research funding from Medtronic UK. No other conflict of interest to declare.
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