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European Journal of Heart Failure 2007 9(8):802-807; doi:10.1016/j.ejheart.2007.05.001
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© 2007 European Society of Cardiology

Left atrial enlargement and NT-proBNP as predictors of sudden cardiac death in patients with heart failure

Antoni Bayes-Genisa,*, Rafael Vazquezb, Teresa Puigc, Carlos Fernandez-Palomequed, Jordi Fabregata, Alfredo Bardajíe, Domingo Pascual-Figalf, Jordi Ordoñez-Llanosg, Mariano Valdesf, Albert Gabarrúsc, Ricardo Pavonb, Luis Pastorb, Jose Ramon Gonzalez Juanateyh, Jesus Almendrali, Miquel Fiolg, Vicente Nietoj, Carlos Macayak, Juan Cincaa, Antoni Bayes de Lunaa and for the MUSIC Study Group

a Cardiology Service, Hospital Santa Creu i Sant Pau-ICCC Barcelona, Spain
b Cardiology Service, Hospital de Valme Seville, Spain
c Epidemiology Service, Hospital Santa Creu i Sant Pau Barcelona, Spain
d Cardiology Service, Hospital Son Dureta Palma de Mallorca, Spain
e Cardiology Service, Hospital Joan XXIII Tarragona, Spain
f Cardiology Service, Hospital Virgen Arrixaca Murcia, Spain
g Biochemistry Service, Hospital Santa Creu i Sant Pau Barcelona, Spain
h Cardiology Service, Hospital Universitario Santiago de Compostela Spain
i Cardiology Service, Hospital Gregorio Marañon Madrid, Spain
j Cardiology Service, Hospital Insular, Las Palmas de Gran Canaria Spain
k Cardiology Service, Hospital Clínico Madrid, Spain

* Corresponding author. Servei de Cardiologia-ICCC, Hospital Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona, St. Antoni Ma. Claret 167, 08025 Barcelona, Spain. E-mail address: abayesgenis{at}santpau.es


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: The identification of valuable markers of sudden cardiac death (SCD) in patients with established HF remains a challenge. We sought to assess the value of clinical, echocardiographic and biochemical variables to predict SCD in a consecutive cohort of patients with heart failure (HF) due to systolic dysfunction.

Methods: A cohort of 494 patients with established HF had baseline echocardiographic and NT-proBNP measurements and were followed for 942±323 days.

Results: Fifty patients suffered SCD. Independent predictors of SCD were indexed LA size >26 mm/m2 (HR 2.8; 95% CI 1.5–5.0; p=0.0007), NT-proBNP >908 ng/L (HR 3.1; 95% CI 1.5–6.7; p=0.003), history of myocardial infarction (HR 2.3; 95% CI 1.3–4.1; p=0.007), peripheral oedema (HR 2.1; 95% CI 1.1–3.9; p=0.02), and diabetes mellitus (HR 1.9; 95% CI 1.1–3.3; p=0.03). NYHA functional class, left ventricular ejection fraction and glomerular filtration rate were not independent predictors of SCD in this cohort. Notably, the combination of both LA size >26 mm/m2 and NT-proBNP >908 ng/L increased the risk of SCD (HR 4.3; 95% CI 2.5–7.6; p<0.0001). At 36 months, risk of SCD in patients with indexed LA size ≤26 mm/m2 and NT-proBNP ≤908 ng/L was 3%, while in patients with indexed LA size >26 mm/m2 and NT-proBNP >908 ng/L reached 25% (p<0.0001).

Conclusions: Among HF patients, indexed LA size and NT-proBNP levels are more useful to stratify risk of SCD than other clinical, echocardiographic or biochemical variables. The combination of these two parameters should be considered for predicting SCD in patients with HF.

Key Words: Left atrial enlargement • NT-proBNP • Sudden cardiac death

Received November 22, 2006; Revised March 5, 2007; Accepted May 1, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure (HF) is the only major cardiovascular disorder which is increasing in incidence and prevalence [1]. Despite recent therapeutic advances, the prognosis of HF remains poor [2,3] and patients experience premature death due to pump failure or sudden cardiac death [4,5]. Sudden cardiac death occurs in about 300,000 individuals per year in the United States and represents about one half of the deaths caused by cardiovascular disease [6]. The pathophysiology of sudden cardiac death in HF is multifactorial, but two-thirds of , patients have suffered from a myocardial infarction in the past and have evidence of significant ventricular dysfunction.

Over the past two decades a number of clinical, biochemical, and echocardiographic variables have been identified as important contributors to the prognosis of patients with HF. Clinical factors such as age and NYHA functional class are useful in identifying individuals at high risk of adverse outcome, but with a low sensitivity [7]. Indeed, the proportion of deaths that are sudden is higher in NYHA class II than class IV patients [4]. Among biochemical variables, plasma natriuretic peptides (BNP and NT-proBNP) have emerged as good markers of cardiac structure and function and cardiovascular prognosis [8,9]. Left ventricular ejection fraction (LVEF) has long been the gold standard for assessing the severity of left ventricular dysfunction and is recognized as a valid surrogate prognostic marker [10]. However, recent reports indicate that LVEF is preserved in over one third of patients admitted with heart failure [11]. Left atrial (LA) size has been found to correlate well with pulmonary artery wedge pressure in HF [12]. Furthermore, studies using LA size measured by echocardiography have demonstrated that LA enlargement predicts mortality and cardiovascular events in patients with cardiovascular disease [13,14].

The MUSIC Study (MUerte Súbita en Insuficiencia Cardiaca) is an observational multicenter study of patients with established HF. This study sought to investigate the relative and incremental prognostic value of clinical, echocardiographic and biochemical variables to predict sudden cardiac death in a consecutive cohort of established HF patients with systolic dysfunction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
494 patients were consecutively enrolled in the MUSIC study at specialist heart failure clinics between April 2003 and December 2004. Patients were followed for a mean of 942±323 days (median 1058) after enrolment. All had established symptomatic HF (New York Heart Association [NYHA] class II-IV) and were treated according to institutional guidelines.

Patients were excluded by recent acute coronary syndrome (within three months) or severe valvular disease amenable for surgical repair. Patients with severe pulmonary (forced expiratory volume in 1s <1L), hepatic or renal (plasma creatinine >250 µmol/L) disease or other concomitant non-cardiovascular diseases expected to reduce life expectancy to less than three years were also excluded. The study was approved by the local Ethics Committee and all patients signed informed consent to participate.

2.2. Study protocol and endpoints
Follow-up visits were conducted on an outpatient basis every six months or according to the patients' clinical status. Detailed information about symptoms, clinical history and 12-lead ECG, medication usage, and therapeutic interventions was collected at each follow-up visit.

An echocardiogram was scheduled for all patients at baseline. Left atrial (LA) diameter was measured by 2-D guided M-mode echocardiography obtained in the parasternal short-axis view at the base of the heart according to the American Society of Echocardiography recommendations [15]. LA size was indexed to body surface area for analysis. LA volume was examined as previously described [16] in a subgroup of patients to assess the correlation between LA diameter and volume. Measurement of LVEF was performed by M-mode or quantitative 2D (Simpson method) as previously described [17]. Patients with reduced LVEF defined as LVEF ≤45% were included in the study. Mitral flow pattern was assessed as previously described and validated [18].

Sudden cardiac death (SCD) was the primary endpoint. For all deaths, the cause was verified from hospital and autopsy records and by either relatives or the primary physician who had witnessed the death. Cardiovascular deaths (CVDs) were defined as "sudden" or "non-sudden" by two independent investigators. Death was defined as "sudden" if it was: 1) a witnessed death occurring within 60 min from the onset of new symptoms, unless a cause other than cardiac was obvious; 2) an unwitnessed death (<24 h) in the absence of pre-existing progressive circulatory failure or other causes of death; or 3) a death during attempted resuscitation [19]. Deaths due to end-stage heart failure were defined as those occurring in hospitals as a result of refractory progressive pump failure. All-cause CVD included SCD and end-stage heart failure. Follow-up data were obtained by regular visits, telephone calls and from hospital records.

2.3. NT-proBNP assay
Blood samples were obtained at enrolment and processed as previously described [20]. Briefly, serum was separated by centrifugation at 1500 g and stored at –80 °C until analysis. NT-proBNP was measured by electrochemiluminescence immunoassay on an Elecsys 1010 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). The intraassay coefficient of variation for NT-proBNP was 1.8% for 221 ng/L and 3.1% for 4250 ng/L; the interassay coefficient of variation was 5.5% for 187 ng/L, 7.0% for 3120 ng/L and 7.3% for 12,376 ng/L.

2.4. Statistical analysis
Descriptive analyses were performed at the first step. Categorical variables were described as frequencies or percentages. Continuous variables were described as means and standard deviations. Relationships between categorical variables were studied using the chi-square test. The comparison of continuous variables between two groups was carried out using the Student's t test for unpaired data once normality was demonstrated (Shapiro-Wilks test); otherwise, the nonparametric test (Mann-Whitney U test) was used. Linear regression analysis was performed to determine the relationship between LA volume and LA diameter. Receiver Operating Characteristic (ROC) curves were constructed to determine the best cut-points for indexed LA size and NT-proBNP. We dichotomized the combination of these two parameters as indexed LA size >best cut-point and NT-proBNP >best cut-point and vice-versa. The associations of the demographic, clinical, echocardiographic and biochemical variables with outcome were assessed by using the Cox proportional hazards models. Variables that showed a significant result univariately (p<0.1) were included in the multivariate Cox backward stepwise model to determine which of them were independently related to prognosis. Simple imputations of random effects were used, if necessary, for variables with missing values. Survival curves were obtained using the Kaplan-Meier method and compared using the log-rank test. Patients who underwent cardiac transplantation or who were lost to follow-up, were censored in the survival analysis. All the analyses were performed using SPSS for Windows (version 14), a 2-sided p-value<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Study population
Of the 494 patients enrolled in the study, 14 received a cardiac transplant and 5 were lost to follow-up. The mean age was 63±11 years, 78% of the patients were male and half of the patients had ischaemic cardiomyopathy. Most patients (75%) were in NYHA functional class II at the time of enrolment into the study. At baseline patients were treated with ACE inhibitors (76%), ARBs (18%), diuretics (78%), beta-blockers (67%), spironolactone (43%) and digoxin (34%). Eight patients had an ICD at inclusion.

The 36-month all-cause cardiovascular death rate was 18% (88/494). Fifty patients experienced SCD and 38 patients had end-stage heart failure. Table 1 shows the demographic, clinical, biochemical and echocardiographic characteristics for the survivors (n=406) and the SCD patients (n=50). SCD patients more often had a prior history of MI (p<0.01), a larger proportion were diabetics (p<0.05) and more often had peripheral oedema (p<0.01). The ECG was in atrial fibrillation-flutter in 14% of survivors and in 28% of SCD patients (p<0.05). Among biochemical variables, haemoglobin and eGFR were significantly lower (p<0.01 and p<0.001, respectively) and NT-proBNP higher in SCD patients (p<0.0001). Echocardiography revealed that LVEDD, LVESD, and LVEF were not significantly different in the SCD patients. Conversely, LA was significantly enlarged, both in absolute values (p<0.0001) or indexed LA size (p<0.0001) in SCD patients (Table 1).


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  		Table 1 Demographic, clinical, biochemical and echocardiographic characteristics of study patients at baseline

 
LA volume was assessed in a subgroup of 63 patients and a significant positive association was found between LA diameter and LA volume (r=0.67, p<0.0001).

3.2. Sudden cardiac death analysis
Using ROC analysis, the optimal cut-point for indexed LA size was 26 mm/m2 (58% sensitivity, 74% specificity, 2.2 positive likelihood ratio — PLR, and 0.6 negative likelihood ratio — NLR) and for NT-proBNP concentration was 908 ng/L (81% sensitivity, 55% specificity, 1.8 PLR and 0.3 NLR). The combination of both LA size and NT-proBNP had 47% sensitivity, 81% specificity, 2.4 PLR and 0.7 NLR.

Statistically significant variables in the univariate analysis (Table 2) were included in the multivariate Cox backward stepwise model to identify those variables independently related to prognosis. In multivariate analysis (Table 3A) the independent predictors of SCD were indexed LA size >26 mm/m2 (HR 2.8, 95% CI 1.5-5.0, p=0.0007), NT-proBNP >908 ng/L (HR 3.1, 95% CI 1.5-6.7, p=0.003), history of MI (HR 2.3, 95% CI 1.3-4.1, p=0.007), peripheral oedema (HR 2.1, 95% CI 1.1-3.9, p=0.02), and diabetes mellitus (HR 1.9, 95% CI 1.1-3.3, p=0.03). Notably, the combination of both LA size >26 mm/m2 and NT-proBNP >908 ng/L significantly increased the risk of SCD (HR 4.3, 95% CI 2.5-7.6; p<0.0001) as shown in Table 3B.


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  		Table 2 Significant univariate association between demographic, clinical, biochemical and echocardiographic characteristics of patients and incidence of SCD during follow-up

 


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  		Table 3 Multivariate analysis utilizing A) individual and B) combined measures of LA size and NT-proBNP for the prediction of SCD

 
Kaplan Meier survival curves depicting SCD rates as a function of indexed LA size and NT-proBNP are shown in Fig. 1. At 36 months, risk of SCD in patients with LA size <26 mm/m2 and NT-proBNP ≤908 ng/L was 3%, while in patients with LA size >26 mm/m2 and NT-proBNP >908 ng/L it reached 25% (p<0.0001). Patients with an enlarged atrium and low NT-proBNP or small atrium and high NT-proBNP had intermediate outcomes.


Figure 01
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  		Fig. 1 Kaplan-Meier survival curves as a function of LA dimension and NT-proBNP.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The results from this study have important clinical implications. After adjustment for clinical, biochemical and echocardiographic variables, LA size and NT-proBNP emerged as good surrogate risk markers of SCD in a consecutive population cohort of outpatients with HF followed for a median of 1058 days. Indeed, when indexed LA size and NT-proBNP levels, either alone or in combination, were added to the multivariate Cox model, conventional predictors of survival such as ejection fraction, eGFR, left bundle branch block, and age were no longer predictive.

The association of left ventricular remodelling (and subsequent HF) with LA enlargement is well established, although the mechanism whereby left ventricular remodelling induces LA dilation may be multifactorial. The left atrium, anatomically delineated by a thin and floppy atrial wall, is prone to dilation and remodelling by the effect of both pressure or volume overload. In patients with reduced ejection fraction, volume overload secondary to mitral regurgitation and elevated left ventricular filling pressures are well recognized to be associated with LA enlargement [12].

Left atrial enlargement is acknowledged as a precise surrogate of cardiovascular mortality but no data is available with regard to its prognostic power in SCD [21]. In patients with left ventricular systolic dysfunction, left atrial area >18 cm2 was found to be an independent and additional predictor of fatal outcome [22]. A sub-analysis of the SOLVD study, which analyzed the prognostic impact of LV mass, LV ejection fraction and LA size in patients with left ventricular dysfunction, confirmed the association between LA enlargement and increased risk of death [23]. In patients with dilated cardiomyopathy enlarged LA was also found to be an independent predictor of all-cause cardiovascular mortality [14,24]. In our study, indexed LA size (>26 mm/m2), a routinely performed echocardiographic measurement, emerged as a powerful surrogate risk marker of SCD in a cohort of patients with HF and systolic dysfunction. Moreover, we found a good correlation between LA diameter and LA volume. Recent evidence suggests that LA volume is a superior measure over LA diameter for predicting outcomes [25]. The extent of reversibility of LA enlargement with therapy and whether regression of LA size translates into improved outcomes is, as yet, unknown and deserves specifically designed prospective studies.

Elevated circulating NT-proBNP levels were also associated with increased risk of subsequent SCD, independent of clinical variables and LVEF. The combination of LA size (≤ or >26 mm/m2) and NT-proBNP (above or below 908 mg/L) was useful to identify the subgroups with highest and lowest mortality. Small LA and low NT-proBNP were associated with a 36-month SCD rate of 3%; enlarged LA and high NT-proBNP resulted in an 8-fold increase in SCD. This finding is not surprising since previous studies have found a strong association between natriuretic peptides and sudden cardiac death [18,26]. Nevertheless, our findings point out for the first time that a combined strategy including LA size and NT-proBNP concentration may be more effective to identify high-risk patients. The combination of both variables was associated with lower sensitivity, but with high specificity and a higher likelihood for predicting SCD. Indeed, both LA size and NT-proBNP concentrations increase in response to a variety of ventricular disorders both associated with volume or pressure overload.

Variables from non-invasive 24-hour ECG recordings (heart rate variability, T wave alternans, etc) have also been evaluated as predictors of SCD. Rashba et al. found that patients with severely depressed heart rate variability had the highest mortality [27]. Future studies are required to assess the predictive usefulness of combining LA size, NT-proBNP and autonomic dysfunction variables.

History of MI was also associated with an increased risk of death after adjusting for clinical and echocardiographic variables. A significant proportion of post-MI patients, even with adequate treatment, are at high risk of dying soon after the acute episode. In the Framingham Study, heart failure alone increased the risk of sudden death fivefold, and in those who had coronary artery disease there was a further doubling of risk [28]. Interestingly, Moller et al. [29] reported that LA enlargement was the most potent predictor of mortality in patients with acute myocardial infarction.

In conclusion, enlarged LA size and high NT-proBNP levels are more useful for stratifying risk of SCD in HF patients than other clinical, echocardiographic or biochemical variables. The utility of LA size and NT-proBNP for monitoring risk of SCD and for guiding therapy needs further research.


   Acknowledgement
 
This study was supported by Redes Temáticas de Investigación Cooperativa; Red de Grupos G03/078; Ministry of Health, Spain.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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