acute heart failure ( ahf ) is one of the leading causes of unscheduled hospitalization in patients older than 65  years and is associated with frequent readmissions and substantial mortality.1 in recent years , several factors that may contribute to exacerbation of heart failure have been identified . among these , acute coronary syndrome , arrhythmias and acute respiratory disease have been identified as being the most common precipitating factors.2 , 3 , 4 , 5 as shown in the analysis of the optimizehf registry , which included patients admitted for ahf in 259 centres in the united states , precipitating factors of ahf influenced shortterm outcome.2 in particular , acute coronary syndrome and acute respiratory disease were associated with higher inhospital mortality . in contrast , little evidence is available about the effect of precipitating factors on readmission and longterm mortality . we recently showed that the effect on outcome of several prognostic factors was strongly influenced by age and was more pronounced in ahf patients younger than 75  years , compared with the older ones.6 the aim of the present study was to assess the effect of precipitating factors of ahf on readmission and longterm mortality in the overall population of patients admitted for ahf and in the subgroup of patients aged 75  years or younger . the  biomarcoeur cohort included patients aged 18  years or older admitted to the emergency department of three tertiary centres ( lariboisire university hospital in paris , france , fattouma bourguiba university hospital in monastir , tunisia , and cumhuriyet university hospital in sivas , turkey ) between 1 january 2010 and 31 december 2013 . ahf ( including de novo ahf , acute decompensated heart failure or cardiogenic shock ) was diagnosed by reviewing medical records after hospital discharge and was based on medical history , clinical examination , natriuretic peptides and additional tests obtained during hospitalization . precipitating factors of ahf were assessed and classified in four main groups : acute coronary syndrome , atrial fibrillation with rapid ventricular conduction , acute pulmonary disease ( including chronic obstructive pulmonary disease exacerbation , asthma and pulmonary infection ) and other causes . the latter group includes undetermined precipitating factors and all precipitating factors not fitting in the previous three categories . the diagnosis of ahf in this cohort has been previously shown to be highly accurate.7 as detailed data about acute pulmonary disease were not included in the original database , the adjudication committee verified and confirmed the combination of ahf and acute pulmonary disease.7 followup visits were performed by phone contact at 1 , 3 , 6 and 12  months after hospital discharge . hospital readmission during 90  days after hospital discharge and survival at 1  year after admission were analysed . the study was carried out in accordance with the declaration of helsinki and was approved by the institutional review board of each centre . the effects of the presence compared with absence of every precipitating factor on 1  year mortality and 90  days readmission rates were assessed using cox regression models without and with adjustment for potential confounding factors ( age , sex and impaired renal function , defined as egfr  <  60  ml / min/1.73  m ) . moreover , the effect of precipitating factors was assessed in the subgroups of patients older than 75  years and aged of 75  years or younger . mortality and readmission were described with the kaplan  meier curve , and differences between groups were assessed by the logrank test . values are expressed as median ( interquartile range ) or as number ( percentage ) , as appropriate . the  biomarcoeur cohort included patients aged 18  years or older admitted to the emergency department of three tertiary centres ( lariboisire university hospital in paris , france , fattouma bourguiba university hospital in monastir , tunisia , and cumhuriyet university hospital in sivas , turkey ) between 1 january 2010 and 31 december 2013 . ahf ( including de novo ahf , acute decompensated heart failure or cardiogenic shock ) was diagnosed by reviewing medical records after hospital discharge and was based on medical history , clinical examination , natriuretic peptides and additional tests obtained during hospitalization . precipitating factors of ahf were assessed and classified in four main groups : acute coronary syndrome , atrial fibrillation with rapid ventricular conduction , acute pulmonary disease ( including chronic obstructive pulmonary disease exacerbation , asthma and pulmonary infection ) and other causes . the latter group includes undetermined precipitating factors and all precipitating factors not fitting in the previous three categories . the diagnosis of ahf in this cohort has been previously shown to be highly accurate.7 as detailed data about acute pulmonary disease were not included in the original database , the adjudication committee verified and confirmed the combination of ahf and acute pulmonary disease.7 followup visits were performed by phone contact at 1 , 3 , 6 and 12  months after hospital discharge . hospital readmission during 90  days after hospital discharge and survival at 1  year after admission were analysed . the study was carried out in accordance with the declaration of helsinki and was approved by the institutional review board of each centre . the effects of the presence compared with absence of every precipitating factor on 1  year mortality and 90  days readmission rates were assessed using cox regression models without and with adjustment for potential confounding factors ( age , sex and impaired renal function , defined as egfr  <  60  ml / min/1.73  m ) . moreover , the effect of precipitating factors was assessed in the subgroups of patients older than 75  years and aged of 75  years or younger . values are expressed as median ( interquartile range ) or as number ( percentage ) , as appropriate . the median age was 75 ( 6484 ) years , 56% of patients were men and clinical signs of congestion were commonly reported : the respiratory rate was 26 per minute ( 2232 per minute ) , rales were audible during lung auscultation of 582 patients ( 82% ) , peripheral edema and jugular distention were reported in 431 ( 57% ) and 310 ( 41% ) patients , respectively . concerning precipitating factors of ahf , acute coronary syndrome was present in 47 patients ( 6% ) , atrial fibrillation with rapid ventricular response in 127 patients ( 17% ) and acute pulmonary disease in 149 patients ( 20% ) . in 459 patients ( 61% ) , ahf was precipitated by other causes . of note , in 27 patients ( 4% ) , a combination of acute coronary syndrome and atrial fibrillation was identified as precipitating factor . baseline characteristics at admission of patients with ahf acei , angiotensin converting enzyme inhibitor ; ahf , acute heart failure ; arb , angiotensin receptor blocker ; bnp , brain natriuretic peptide ; cabg , coronary artery bypass grafting ; copd , chronic obstructive pulmonary disease ; crp , creactive protein ; dbp , diastolic blood pressure ; egfr , estimated glomerular filtration rate ; mra , mineralocorticoid receptor antagonist ; pci , percutaneous coronary intervention ; sbp , systolic blood pressure . as summarized in table 
 1 , patients with ahf precipitated by acute pulmonary disease were older ( 78  years vs. 73  years ) , reported more often previous history of chronic obstructive pulmonary disease or asthma ( 42% vs. 12% ) , suffered from greater respiratory impairment ( higher respiratory rate and lower peripheral oxygen saturation ) and showed more often wheezing on lung auscultation ( 44% vs. 13% ) than patients with ahf precipitated by nonpulmonary causes . as illustrated in figure 
 1 , patients with ahf precipitated by acute pulmonary disease had higher levels of creactive protein [ 35  mg / l ( 10110  mg / l ) vs. 14  mg / l ( 531  mg / l ) , p  <  0.001 ] but lower levels of bnp [ 899  pg / ml ( 4041445  pg / ml ) vs. 1191  pg / ml ( 6432329  pg / ml ) , p  <  0.001 ] compared with the group of ahf precipitated by nonpulmonary causes . levels of bnp and crp ( creactive protein ) at admission in the group of patients with acute heart failure precipitated by acute pulmonary disease ( n  =  149 ) compared with acute heart failure precipitated by nonpulmonary causes ( n  =  606 ) . median and 95% confidence interval are displayed . precipitating factors significantly influenced the 90  days readmission rates , as shown in table 
 2 . in the overall population , acute pulmonary disease was associated with lower readmission rates ( hazard ratio ( hr ) 0.61 , 95% confidence interval ( ci ) 0.370.99 , p  =  0.049 ) , whereas atrial fibrillation with rapid ventricular response , acute coronary syndrome and other precipitating factors showed a nonsignificant trend towards higher readmission rates . after adjustment for potential confounding factors , none of the precipitating factors significantly influenced the readmission rates . as shown in figure 
 2 ( left panel ) , the subgroup of patients with ahf precipitated by acute pulmonary disease ( n  =  149 ) showed fewer readmissions ( logrank p  =  0.047 ) compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( n  =  606 ) . precipitating factors and risk of 90  days readmission ahf , acute heart failure ; ci , confidence interval . risk of 90  days readmission in presence of predefined classes of precipitating factors of ahf compared with absence of the same factor . readmissions of patients with acute heart failure precipitated by acute pulmonary disease compared with acute heart failure precipitated by nonpulmonary causes during 90  days after discharge in the overall population and in the subgroup of patients 75  years . in the subgroup of patients aged 75  years or younger , differences were even more pronounced : as shown in table 
 2 , after adjustment for potential confounding factors , acute pulmonary disease was associated with markedly lower readmission rates ( hr 0.20 , 95% ci 0.060.63 , p  =  0.006 ) , whereas atrial fibrillation ( hr 2.23 , 95% ci 1.293.85 , p  =  0.004 ) and acute coronary syndrome ( hr 2.23 , 95% ci 1.024.86 , p  =  0.044 ) were associated with higher readmission rates . as illustrated in figure 
 2 ( right panel ) , younger patients with ahf precipitated by acute pulmonary disease showed fewer readmissions compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( logrank p  =  0.003 ) . as shown in table 
 3 , acute pulmonary disease at admission was associated with higher mortality at 1  year in the overall population ( hr 1.59 , 95% ci 1.042.43 , p  =  0.034 ) , whereas all three other groups of precipitating factors were not . after adjustment for potential confounding factors , acute pulmonary disease showed only a nonsignificant trend towards higher risk of death in the overall population ( hr 1.46 , 95% ci 0.942.25 , p  =  0.09 ) . as illustrated in figure 
 3 ( left panel ) , patients with ahf precipitated by acute pulmonary disease showed increased mortality during 1  year followup compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( logrank p  =  0.032 ) . precipitating factors and risk of 1  year mortality ahf , acute heart failure ; ci , confidence interval . risk of 1  year mortality in presence of predefined classes of precipitating factors of ahf compared with absence of the same factor . mortality of patients with acute heart failure precipitated by acute pulmonary disease compared with acute heart failure precipitated by nonpulmonary causes during 1  year after admission in the overall population and in the subgroup of patients 75  years . more interestingly , in the subgroup of patients aged 75  years or younger , acute pulmonary disease was associated with significantly higher risk of death ( hr 2.52 , 95% ci 1.175.41 , p  =  0.018 ) . as illustrated in figure 
 3 ( right panel ) , younger patients with ahf precipitated by acute pulmonary disease showed higher mortality compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( logrank p  =  0.026 ) . the median age was 75 ( 6484 ) years , 56% of patients were men and clinical signs of congestion were commonly reported : the respiratory rate was 26 per minute ( 2232 per minute ) , rales were audible during lung auscultation of 582 patients ( 82% ) , peripheral edema and jugular distention were reported in 431 ( 57% ) and 310 ( 41% ) patients , respectively . concerning precipitating factors of ahf , acute coronary syndrome was present in 47 patients ( 6% ) , atrial fibrillation with rapid ventricular response in 127 patients ( 17% ) and acute pulmonary disease in 149 patients ( 20% ) . in 459 patients ( 61% ) , ahf was precipitated by other causes . of note , in 27 patients ( 4% ) , a combination of acute coronary syndrome and atrial fibrillation was identified as precipitating factor . baseline characteristics at admission of patients with ahf acei , angiotensin converting enzyme inhibitor ; ahf , acute heart failure ; arb , angiotensin receptor blocker ; bnp , brain natriuretic peptide ; cabg , coronary artery bypass grafting ; copd , chronic obstructive pulmonary disease ; crp , creactive protein ; dbp , diastolic blood pressure ; egfr , estimated glomerular filtration rate ; mra , mineralocorticoid receptor antagonist ; pci , percutaneous coronary intervention ; sbp , systolic blood pressure . as summarized in table 
 1 , patients with ahf precipitated by acute pulmonary disease were older ( 78  years vs. 73  years ) , reported more often previous history of chronic obstructive pulmonary disease or asthma ( 42% vs. 12% ) , suffered from greater respiratory impairment ( higher respiratory rate and lower peripheral oxygen saturation ) and showed more often wheezing on lung auscultation ( 44% vs. 13% ) than patients with ahf precipitated by nonpulmonary causes . as illustrated in figure 
 1 , patients with ahf precipitated by acute pulmonary disease had higher levels of creactive protein [ 35  mg / l ( 10110  mg / l ) vs. 14  mg / l ( 531 mg / l ) , p  <  0.001 ] but lower levels of bnp [ 899  pg / ml ( 4041445  pg / ml ) vs. 1191  pg / ml ( 6432329  pg / ml ) , p  <  0.001 ] compared with the group of ahf precipitated by nonpulmonary causes . levels of bnp and crp ( creactive protein ) at admission in the group of patients with acute heart failure precipitated by acute pulmonary disease ( n  =  149 ) compared with acute heart failure precipitated by nonpulmonary causes ( n  =  606 ) . median and 95% confidence interval are displayed . precipitating factors significantly influenced the 90  days readmission rates , as shown in table 
 2 . in the overall population , acute pulmonary disease was associated with lower readmission rates ( hazard ratio ( hr ) 0.61 , 95% confidence interval ( ci ) 0.370.99 , p  =  0.049 ) , whereas atrial fibrillation with rapid ventricular response , acute coronary syndrome and other precipitating factors showed a nonsignificant trend towards higher readmission rates . after adjustment for potential confounding factors , none of the precipitating factors significantly influenced the readmission rates . as shown in figure 
 2 ( left panel ) , the subgroup of patients with ahf precipitated by acute pulmonary disease ( n  =  149 ) showed fewer readmissions ( logrank p  =  0.047 ) compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( n  =  606 ) . precipitating factors and risk of 90  days readmission ahf , acute heart failure ; ci , confidence interval . risk of 90  days readmission in presence of predefined classes of precipitating factors of ahf compared with absence of the same factor . readmissions of patients with acute heart failure precipitated by acute pulmonary disease compared with acute heart failure precipitated by nonpulmonary causes during 90  days after discharge in the overall population and in the subgroup of patients 75  years . in the subgroup of patients aged 75  years or younger , differences were even more pronounced : as shown in table 
 2 , after adjustment for potential confounding factors , acute pulmonary disease was associated with markedly lower readmission rates ( hr 0.20 , 95% ci 0.060.63 , p  =  0.006 ) , whereas atrial fibrillation ( hr 2.23 , 95% ci 1.293.85 , p  =  0.004 ) and acute coronary syndrome ( hr 2.23 , 95% ci 1.024.86 , p  =  0.044 ) were associated with higher readmission rates . as illustrated in figure 
 2 ( right panel ) , younger patients with ahf precipitated by acute pulmonary disease showed fewer readmissions compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( logrank p  =  0.003 ) . as shown in table 
 3 , acute pulmonary disease at admission was associated with higher mortality at 1  year in the overall population ( hr 1.59 , 95% ci 1.042.43 , p  =  0.034 ) , whereas all three other groups of precipitating factors were not . after adjustment for potential confounding factors , acute pulmonary disease showed only a nonsignificant trend towards higher risk of death in the overall population ( hr 1.46 , 95% ci 0.942.25 , p  =  0.09 ) . as illustrated in figure 
 3 ( left panel ) , patients with ahf precipitated by acute pulmonary disease showed increased mortality during 1  year followup compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( logrank p  =  0.032 ) . precipitating factors and risk of 1  year mortality ahf , acute heart failure ; ci , confidence interval . risk of 1  year mortality in presence of predefined classes of precipitating factors of ahf compared with absence of the same factor . adjustment was performed for age , sex and impaired renal function . no risk calculation possible because of lack of events in this subgroup . mortality of patients with acute heart failure precipitated by acute pulmonary disease compared with acute heart failure precipitated by nonpulmonary causes during 1  year after admission in the overall population and in the subgroup of patients 75  years . more interestingly , in the subgroup of patients aged 75  years or younger , acute pulmonary disease was associated with significantly higher risk of death ( hr 2.52 , 95% ci 1.175.41 , p  =  0.018 ) . as illustrated in figure 
 3 ( right panel ) , younger patients with ahf precipitated by acute pulmonary disease showed higher mortality compared with the subgroup of patients with ahf precipitated by nonpulmonary causes ( logrank p  =  0.026 ) . the influence of precipitating factors on outcome , described in the present paper , extends the concept proposed by fonarow and coworkers after analysis of the optimizehf registry.2 fonarow and coworkers showed an association between acute coronary syndrome ( acs ) , pulmonary infection and higher inhospital mortality , but no data exist on the influence of precipitating factors on postdischarge readmissions and longterm mortality . the present study demonstrated that precipitating factors of ahf may substantially influence outcome far beyond the duration of hospitalization , especially in patients aged 75  years or younger : readmission rates were low when acute pulmonary disease precipitated ahf and high when nonacute pulmonary disease , including atrial fibrillation or acute coronary syndrome , precipitated ahf . the influence of precipitating factors of ahf on postdischarge readmission rate , in patients aged 75  years or younger , is a novel observation . the existence of congestion is a frequent cause of hospital readmission in patients with chronic heart failure.8 in the present study , the subgroup with acute pulmonary disease , as precipitating cause of ahf , showed lower levels of bnp suggesting a lower level of congestion compared with patients with nonpulmonary precipitating factors . furthermore , patients with acute pulmonary diseases , including infections , once treated , are usually discharged home with rare readmissions . the influence of acute pulmonary disease on postdischarge readmission rate was mostly seen in patients aged 75  years or younger , while no influence of precipitating factors on readmissions in older ahf patients . we recently showed that effect of several prognostic factors was influenced by age and was more pronounced in ahf patients younger than 75  years , compared with the older ones.6 results of the present study confirm the stronger relationship between prognostic factors and outcome in younger patients , although the reasons remain unknown : a more complex interaction between precipitating factors , multimorbidity and frailty of older patients with ahf could be a reasonable explanation . surprisingly , the observed influence of acute pulmonary disease on longterm mortality was divergent from that on readmission : patients with ahf exacerbated by acute pulmonary disease showed higher mortality . two recently published studies showed that pneumonia is associated with increased risk for cardiovascular events after hospital discharge.9 , 10 a combination of endothelial dysfunction , plaque instability , activated coagulation,11 volume overload , inflammatory and ischemic myocardial injury12 and arrhythmias13 have been postulated to explain increased morbidity and mortality . it is still unclear whether the adverse prognosis of the subgroup of admitted for ahf precipitated by acute pulmonary disease is caused by the unfavourable association of ahf and pulmonary disease itself or is rather a marker of a more complex comorbidity profile in patients with such an association . our study suggests that the peculiar pathophysiological background of ahf precipitated by acute pulmonary disease exposes those patients to increased risk of death despite fewer readmissions . as a consequence , those patients should benefit not only from aggressive initial treatment but also from a more intensive and interdisciplinary followup after hospital discharge . the study was conducted on a mediumsized cohort of patients with ahf from three tertiary centres . therefore , the conclusions of this study should be confirmed in larger cohorts . however , this cohort was large enough to demonstrate significant differences between the different precipitating factors . moreover , the group of  other precipitating factors was quite large , as our database was not conceived for further differentiation among other causes of ahf . this group might include patients with ahf precipitated by other causes as hypertension , malcompliance and worsening renal function.3 , 4 , 5 despite outcome data were derived from telephonic followup and relevant censoring ( 287 patients , 38% ) occurred , the median followup in the cohort was 320  days . in addition , the cause of readmission was not assessed during followup , and therefore , the risk of a potential bias derived from newonset precipitating factors , although small , can not be excluded . in particular , patients with ahf precipitated by acute pulmonary disease showed fewer readmissions and higher 1  year mortality , especially in patients aged 75  years or younger .
abstractaimsacute heart failure ( ahf ) is one of the leading causes of unscheduled hospitalization and is associated with frequent readmissions and substantial mortality . precipitating factors of ahf influence shortterm mortality , but their effect on outcome after hospital discharge is unknown . 
 the present study assessed the effect of precipitating factors on readmission and longterm survival in the overall population and in patients aged 75  years or younger.methods and resultspatients admitted with ahf ( n  =  755 ) included in the multicentre cohort 
 biomarcoeurs were included in the study . precipitating factors of ahf 
 were classified in four main groups : acute coronary syndrome , atrial fibrillation , acute pulmonary disease and other causes . 
 hospital readmission during 90  days after discharge and survival at 1  year were analysed . precipitating factors influenced readmissions and survival . 
 acute pulmonary disease was associated with fewer readmissions ( hr 0.61 , 95% confidence interval ( ci ) 0.370.99 , p  =  0.049 ) , especially in patients aged 75  years or younger ( hr 0.20 , 95% ci 0.060.63 , p  =  0.006 ) , whereas atrial fibrillation ( hr 2.23 , 95% ci 1.293.85 , p  =  0.004 ) and acute coronary syndrome ( hr 2.23 , 95% ci 1.024.86 , p  =  0.044 ) were associated with more readmissions . 
 patients with acute pulmonary disease at admission showed higher mortality ( hr 1.59 , 95% ci 1.042.43 , p  =  0.034 ) , especially in subjects aged 75  years or younger ( hr 2.52 , 95% ci 1.175.41 , p  =  0.018).conclusionsprecipitating factors of ahf substantially influenced outcome after hospitalization . in particular , patients with ahf precipitated by acute pulmonary disease showed fewer readmissions and higher 1  year mortality , especially in patients aged 75  years or younger .