Weston, Susan A.

Background— Heart failure (HF) can occur in patients with preserved (HFpEF, EF≥50%) or reduced (HFrEF, EF<50%) ejection fraction (EF), but changes in EF after HF diagnosis are not well described. Methods and Results— Among a community cohort of incident HF patients diagnosed from 1984 to 2009 in Olmsted County, Minnesota, we obtained all EFs assessed by echocardiography from initial HF diagnosis until death or last follow-up through March 2010. Mixed effects models fit a unique linear regression line for each person using serial EF data. Compiled results allowed estimates of the change in EF over time in HFpEF and HFrEF. Among 1233 HF patients (48.3% male, mean age 75.0 years, mean follow-up 5.1 years), 559 (45.3%) had HFpEF at diagnosis. In HFpEF, on average, EF decreased by 5.8% over 5 years ( P <0.001) with greater declines in older individuals and those with coronary disease. Conversely, EF increased in HFrEF (average increase 6.9% over 5 years, P <0.001). Greater increases were noted in women, younger patients, individuals without coronary disease, and those treated with evidence-based medications. Overall, 39% of HFpEF patients had an EF<50% and 39% of HFrEF patients had an EF≥50% at some point after diagnosis. Decreases in EF over time were associated with reduced survival whereas increases in EF were associated with improved survival. Conclusions— These data suggest that progressive contractile dysfunction may contribute to the pathophysiology of HFpEF. Prospective longitudinal studies are needed to confirm these observations and establish the mechanism and clinical relevance of decline in EF over time in HFpEF.

Background— Heart failure (HF) and atrial fibrillation (AF) share common risk factors and often coexist. The combination of HF and AF may carry a worse prognosis than either condition alone; however, the magnitude of this risk remains controversial and it is not known whether the timing of AF influences the risk of death. Methods and Results— We determined the risk of all-cause mortality in relation to the presence of AF prior to or after HF diagnosis in a community-based cohort of persons diagnosed as having HF between 1983 and 2006. Of 1664 individuals with HF, 553 had a history of AF and 384 developed AF after HF. During a median follow-up of 4.0 years, 450 deaths occurred among persons with prior AF, 314 among those with AF after HF, and 572 among patients without AF. In fully adjusted models, compared with patients without AF, those with AF prior to HF had a 29% increased risk of death, whereas those who developed AF after HF exhibited >2-fold increased risk of death. Conclusions— In the community, AF is frequent in the setting of HF and is associated with a large excess risk of death. The magnitude of this excess risk differs markedly according to the timing of AF, with AF developing after HF conferring the largest increased risk of death compared with HF patients without AF.

Background— Data on the association between myocardial infarction (MI) and fractures are scarce. Recent changes in the epidemiology of MI justify exploring this relationship. We evaluated whether MI constitutes a risk factor for osteoporotic fracture and examined secular trends in this association. Methods and Results— Consecutive Olmsted County, Minnesota, residents with incident MI diagnosed in 1979 to 2006 and community control subjects individually matched (1:1) to cases on age, sex, and year of onset (n=6642) were followed up through 2009. Outcome measures were time to osteoporotic fracture, overall and by anatomic site, and death. Fracture incidence rates were stable in controls but increased markedly over time among MI cases. Accordingly, although an overall excess of fracture risk after MI was observed (adjusted hazard ratio, 1.32; 95% confidence interval, 1.12 to 1.56), substantial temporal variations were noted (1979 to 1989: hazard ratio, 0.81; 95% confidence interval, 0.58 to 1.12; 1990 to 1999: hazard ratio, 1.47; 95% confidence interval, 1.10 to 1.96; 2000 to 2006: hazard ratio, 1.73; 95% confidence interval, 1.32 to 2.27; P for trend <0.001). Trends were similar regardless of age, sex or fracture site. Conversely, the overall hazard ratio for death in MI cases versus controls did not change materially despite a continuous decline in 30-day case fatality rate (12.5% in 1979 to 1989; 6.7% in 2000 to 2006). Observed changes in the baseline prevalence of cardiovascular risk factors, MI characteristics, and comorbidities did not fully account for the trends in fracture risk. Conclusions— Over the past decades, the association between MI and osteoporotic fractures increased steadily. The trend is consistent with the displacement of post-MI outcomes toward noncardiovascular events, highlighting the need for comprehensive prevention strategies to accommodate the changing epidemiology of MI.

Background— Atrial fibrillation (AF) often coexists with myocardial infarction (MI), yet its prognostic influence is disputed. Prior reports studied the relationship of AF during early hospitalization for acute MI to the risk of death and could not address the timing of AF in relation to the MI (ie, before, during, after). Furthermore, as data come mostly from clinical trials, their applicability to the community is uncertain. The aims of our study were to assess the occurrence of AF among MI patients, determine whether it has changed over time, and quantify its impact and the impact of its timing on mortality after MI. Methods and Results— This was a community-based cohort of 3220 patients hospitalized with incident (first-ever) MI from 1983 to 2007 in Olmsted County, MN. Atrial fibrillation was identified by diagnostic codes and ECG. Outcomes were all-cause and cardiovascular death. Atrial fibrillation before MI was identified in 304 patients, and 729 developed AF after MI (218 [30%] within 2 days, 119 [16%] between 3 and 30 days, and 392 [54%] >30 days post-MI). The cumulative incidence of AF after MI at 5 years was 19% and did not change over the calendar year of MI (the incidence of AF was the same regardless of when the MI occurred). During a mean follow-up of 6.6 years, 1638 deaths occurred. AF was associated with an increased risk of death (hazard ratio [95% confidence interval] 3.77 [3.37 to 4.21]), independently of clinical characteristics at the time of MI and heart failure. This risk differed markedly according to the timing of AF, and was the greatest for AF occurring >30 days post MI (hazard ratio [95% confidence interval] 1.63 [1.37 to 1.93] for AF within 2 days, 1.81 [0.45 to 2.27] for AF between 3 and 30 days, and 2.58 [2.21 to 3.00] for AF >30 days post MI). Conclusions— In the community, AF is frequent in the setting of MI. Atrial fibrillation carries an excess risk of death, which is the highest for AF developing >30 days after MI.

Background— In 2000, the definition of myocardial infarction (MI) changed to rely on troponin rather than creatine kinase (CK) and its MB fraction (CK-MB). The implications of this change on trends in MI incidence and outcome are not defined. Methods and Results— This was a community study of 2816 patients hospitalized with incident MI from 1987 to 2006 in Olmsted County, Minnesota, with prospective measurements of troponin and CK-MB from August 2000 forward. Outcomes were MI incidence, severity, and survival. After troponin was introduced, 278 (25%) of 1127 incident MIs met only troponin-based criteria. When cases meeting only troponin criteria were included, incidence did not change between 1987 and 2006. When restricted to cases defined by CK/CK-MB, the incidence of MI declined by 20%. The incidence of non–ST-segment elevation MI increased markedly by relying on troponin, whereas that of ST-segment elevation MI declined regardless of troponin. The age- and sex-adjusted hazard ratio of death within 30 days for an infarction occurring in 2006 (compared with 1987) was 0.44 (95% confidence interval, 0.30 to 0.64). Among 30-day survivors, survival did not improve, but causes of death shifted from cardiovascular to noncardiovascular ( P =0.001). Trends in long-term survival among 30-day survivors were similar regardless of troponin. Conclusions— Over the last 2 decades, a substantial change in the epidemiology of MI occurred that was only partially mediated by the introduction of troponin. Non–ST-segment elevation MIs now constitute the majority of MIs. Although the 30-day case fatality improved markedly, long-term survival did not change, and the cause of death shifted from cardiovascular to noncardiovascular.

Background— The relationship between neutrophils and outcomes post–myocardial infarction (MI) is not completely characterized. We examined the associations of neutrophil count with mortality and post-MI heart failure (HF) and their incremental value for risk discrimination in the community. Methods and Results— MI was diagnosed with cardiac pain, biomarkers, and Minnesota coding of the ECG. Neutrophil count at presentation, reported as counts ×10 9 /L, was categorized by tertiles (lower tertile, <5.7; middle tertile, 5.7 to 8.5; upper tertile, >8.5). From 1979 to 2002, 2047 incident MIs occurred in Olmsted County, Minn (mean age, 68±14 years; 44% women). Median (25th to 75th percentile) neutrophil count was 7.0 (5.1 to 9.5). Within 3 years post-MI, 577 patients died, and 770 developed HF. Overall survival and survival free of HF decreased with increased neutrophil tertile ( P <0.001). Compared with the lower tertile, the age and sex adjusted hazard ratio for death was 1.44 (95% CI, 1.14 to 1.81) for the middle tertile and 2.60 (95% CI, 2.10 to 3.22) for the upper tertile ( P <0.001). Similarly, for HF, the hazard ratio was 1.32 (95% CI, 1.09 to 1.59) for the middle and 2.12 (95% CI, 1.77 to 2.53) for the upper tertile ( P <0.001). These associations persisted after adjustment for risk factors, comorbidities, Killip class, revascularization, and ejection fraction. Neutrophil count improved risk discrimination as indicated by increases in the area under the receiver operating characteristic curves (all P <0.05) and by the integrated discrimination improvement analysis (all P <0.001). Conclusions— In the community, the neutrophil count was strongly and independently associated with death and HF post-MI and improved risk discrimination over traditional predictors.

Background— Mortality among patients with heart failure is high. Though individual biomarkers have been investigated to determine their value in mortality risk prediction, the role of a multimarker strategy requires further evaluation. Methods and Results— Olmsted County residents presenting with heart failure from July 2004 to September 2007 were recruited to undergo biomarker measurement. We investigated whether addition of C-reactive protein, B-type natriuretic peptide, and troponin T to a model including established risk indicators improved 1-year mortality risk prediction using the c statistic, integrated discrimination improvement, and net reclassification improvement. Among 593 participants, the mean age was 76.4 years, and 48% were men. After 1 year of follow-up, 122 (20.6%) participants had died. Patients with C-reactive protein (<11.8 mg/L), B-type natriuretic peptide (<350 pg/mL), and troponin T (≤0.01 ng/mL) less than the median had low 1-year mortality (3.3%), whereas those with 2 or 3 biomarkers greater than the median had markedly increased mortality (30.8% and 35.5%, respectively). The addition of 2 or more biomarkers to the model offered greater improvement in 1-year mortality risk prediction than use of a single biomarker. The combination of C-reactive protein and B-type natriuretic peptide resulted in an increase in the c statistic from 0.757 to 0.810 ( P <0.001), an integrated discrimination improvement gain of 7.1% ( P <0.001), and a net reclassification improvement of 22.1% ( P <0.001). Use of all 3 biomarkers offered no incremental gain (integrated discrimination improvement gain 0.7% versus C-reactive protein+B-type natriuretic peptide, P =0.065). Conclusions— Biomarkers improved 1-year mortality risk prediction beyond established indicators. The use of a 2-biomarker combination was superior to a single biomarker in risk prediction, though addition of a third biomarker conferred no added benefit.

Background— Tumor necrosis factor-α (TNFα), an inflammatory cytokine, was reported to be elevated in trials of heart failure (HF) with reduced ejection fraction (EF) and associated with mortality. Whether this is true for HF with preserved EF is unknown, and community data are lacking. We evaluated the distribution of TNFα, its association with baseline characteristics and mortality, and its benefit in assessing risk in community HF patients. Methods and Results— Olmsted County residents with active HF from July 2004 to March 2007 (n=486; mean age, 76.7 years; EF ≥50%, 55%) were prospectively recruited. Clinical characteristics and TNFα were measured. Elevated TNFα (more than the assay limit of normal of 2.8 pg/mL) was present in 143 (29%). Higher TNFα was associated with decreased creatinine clearance, nonsmoking status, anemia, and greater comorbidity ( P trend <0.05 for all). Mortality increased with increasing TNFα ( P =0.016), with 1-year mortality estimates of 16%, 18%, 23%, and 32% from the lowest to highest quartile, respectively. After adjustment for age, sex, and EF, the hazard ratios for death were 1.24, 1.37, and 1.90 from the second to the highest TNFα quartile, respectively ( P trend =0.007). TNFα contributed to risk assessment as indicated by increases in the area under the receiver operating characteristic curves in all models examined ( P <0.05 for all). Results did not differ by EF ( P =0.60 interaction term of TNFα and EF). Conclusions— TNFα was elevated in a large portion of community HF patients, was associated with a large decrease in survival, and provided a significant incremental increase in risk assessment above established indicators. TNFα is useful for risk assessment in HF patients with preserved and reduced EF.

Background— Mortality in patients with heart failure (HF) remains high, but causes of death are incompletely defined. As HF is a heterogeneous syndrome categorized according to the ejection fraction (EF), the association between EF and causes of death is important, yet elusive. Methods and Results— Community subjects with HF were classified according to the preserved (≥50%) and the reduced EF (<50%). Deaths were classified as due to coronary heart disease and other cardiovascular and noncardiovascular diseases. Among 1063 persons with HF, 45% had preserved EF with fewer cardiovascular risk factors and less coronary disease than those with reduced EF. At 5 years, survival was 45% (95% CI, 43% to 49%), and 43% of the deaths were noncardiovascular. The leading cause of death in subjects with preserved EF was noncardiovascular disease (49%) versus coronary heart disease (43%) for subjects with reduced EF. The proportion of cardiovascular deaths decreased from 69% in 1979–1984 to 40% in 1997–2002 ( P =0.007) among subjects with preserved EF, which is in contrast to a modest change among those with reduced EF (77% to 64%, P =0.08). Advanced age, male sex, diabetes, smoking, and kidney disease were associated with an increased risk of all-cause and cardiovascular deaths. After adjustment, preserved EF was associated with a lower risk of cardiovascular death but not all-cause death. Conclusions— Community subjects with HF experience a persistently high mortality, and a large proportion of deaths is noncardiovascular. Cardiovascular disease before death is less in subjects with preserved EF, and they are less likely to experience cardiovascular deaths compared with those with reduced EF. In those with preserved EF, the proportion of cardiovascular deaths declined over time.

We examined trends in heart disease (HD) mortality and the delivery of cardiac in Olmsted County, MN. Between 1979 and 1994, women experienced 51% of the total number of HD (ICD9 codes 390 — 398,402,404 — 429) deaths (3095). Age-adjusted HD mortality rate declined from 123 per 100,000 (95%CI 102, 144) in 1979 to 81 (67,95) in 1994. The risk ratio (RR) of HD death in 1994 compared to 1979 was 0.69 for women vs 0.53 for men (P = 0.06). This equates to a decline in HD mortality of 2.5%=y in women and 4.2%=y in men. The decline in HD mortality was less pronounced in older age groups (P < 0.001), reflecting a shift of the burden of HD towards women and the elderly. Compared to men, there was less use of stress tests among women, of cardiology visits after stress testing, and of cardiac procedures among women presenting to the emergency room with unstable angina. Further studies are needed to examine causal links between these trends.