Clinical Characteristics and Follow Up

All FHS and CHS cohort participants are under continuous surveillance for CVD events and mortality. In addition to in-person examinations, FHS participants complete regular health history updates and questionnaire-based surveys by phone. A panel of three physicians reviews all pertinent medical records to adjudicate CVD outcomes. CHS participants receive similar clinic visits, telephone contacts, and medical record review to adjudicate outcomes.(8) Clinical covariates at or at the closest examination to the incident HF event were recorded in each cohort. In both cohorts, blood pressure was recorded as the average of two measurements obtained in a seated position on resting participants separated by 5 minutes. The occurrence of MI was assessed by integrating the clinical presentation, cardiac biomarkers, and ECG. Diabetes mellitus was defined as fasting blood glucose ≥126 mg/dl, random blood glucose >200 mg/dl, or the use of hypoglycemic agents. Current smoking was considered ≥1 cigarette daily over the past year prior to the cohort examination. Obesity was defined as body mass index ≥30 kg/m².

In the FHS, HF was diagnosed by a physician adjudication panel that reviewed all pertinent inpatient and outpatient medical records, applying FHS criteria that have been consistent over several decades.(9) The CHS Events Committee similarly adjudicated HF events by reviewing documented signs, symptoms, diagnostic test results, and/or medical treatment.(8,10,11) For the events in this analysis, either probable or definite heart failure were considered. The sensitivity and specificity of criteria for HF used in FHS and CHS have been previously reported and found to be comparable with other HF criteria(12) and the FHS and CHS definitions have similar associations with mortality.(13)

We considered the date of onset of HF as any of the following: the first episode of HF symptoms, physician visit documenting HF, or HF hospitalization in both FHS and CHS. For additional analyses, we defined HFREF and HFPEF as HF with LVEF <50% and ≥50%, respectively. This cutoff, utilized by other studies, has been considered by the American Heart Association and European Society of Cardiology reasonable to differentiate the two groups.(2,14–17) LVEF was obtained from medical record review of imaging studies, including transthoracic echocardiograms, radionuclide ventriculograms, and invasive angiocardiograms performed within a year of HF diagnosis for FHS and 30 days for CHS. Participants without an assessment of LVEF performed in proximity to the HF episode were included in the analyses of all-HF but excluded in analyses of HF subtype. We evaluated the incidence of HF (and the two subtypes HFREF vs. HFPEF) during the time period of interest, and considered 5-year follow-up for the outcome of death due to all causes among HF cases. To provide further granularity regarding cause of death, in secondary analysis, we compared the prevalence of CVD- vs. non-CVD death by HF subtype and decade. To understand the specific entities that may have contributed to CVD death, we also examined the prevalence of interim MI and sudden cardiac death within between onset of HF and death.

Incidence of HF, HFREF, and HFPEF during 1990–2009

Overall, 2,524 incident HF events occurred (1,367 in the first decade), of which 844 (33%; 491 in the first decade) were HFREF, 704 (29%; 309 in the first decade) were HFPEF, and 940 (37%, 567 in the first decade) were unclassified HF. The age- and sex-adjusted standardized incidence rates for 1990–1999 and 2000–2009 were 19.7 and 18.9 per 1000 persons, per one-year follow-up, respectively (Table 2). Thus, the overall incidence of HF remained similar over the past two decades. In Poisson models adjusting for age, sex, and cohort, where the first decade = referent, the incidence rate ratio of overall HF was 0.94 (95% CI 0.86–1.02, p=0.13), indicating no significant change in HF incidence between decades, consistent with the rates of standardized HF incidence. In similar Poisson models of HF subtypes, the incidence rate ratio of HFREF was 0.80 (95% CI 0.69–0.93, p=0.0029) and that of HFPEF was 1.53 (95% CI 1.30–1.79, p<0.0001). These results are also consistent with those of standardized HF incidence rates, suggesting the decline in HFREF incidence observed from the first to second decade is significant when additionally accounting for cohort, and confirming the significant rise in HFPEF incidence over this time.

Trends in HF and HF Subtype Incidence by Sex

HF incidence from 1990–2009 is presented by sex in the Figure and Supplemental Table 2. The incidences of all HF and HFREF were greater in men than women in both decades (all p<0.001). The incidence of HFPEF was similar between men and women in both decades (p=0.16 and p=0.08, respectively). The incidence of overall HF decreased by nearly 17% between decades in men (25.5 to 21.2 per 1000 persons, p=0.01), but remained relatively constant in women (16.4 and 16.0 per 1000 persons, p=0.71). Between the two decades, the decline in the incidence of HFREF was largely driven by men, in whom HFREF incidence declined by 30% (12.2 to 8.5 per 1000 persons, p<0.001), as women showed a non-significant decrease (4.6 to 4.1 per 1000 persons, p=0.23). The incidence of HFPEF increased in both sexes over 1990–2009, nearly doubling in men (3.9 to 7.6 per 1000 persons, p<0.001) but still a substantial (29%) increase in women (4.8 to 6.2 per 1000 persons, p=0.02).

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Figure

Incidence of HF and HF subtypes by decade in men and women. Incidence reported standardized to age- and sex-specific 2010 (ages 60–95) US population rates, per 1 year follow up. 95% confidence interval bars shown.

Incidence of Overall HF, HFREF, and HFPEF from 1990–2009 in the Community

Trends in HF incidence have been mixed in past decades, with a decline suggested in Olmsted County.(2,14,19–24) A study of three Danish registries during this time period are also consistent with a mixed picture, with a decline in HF incidence in older individuals but rise in HF incidence in younger individuals.(25) A recent U.K. report suggests a decline in HF incidence over the past decade.(26) Our findings suggest that contemporary HF incidence over the past two decades is relatively unchanged. Differences in the absolute incidence of HF in our study may relate to methodologic and population sample differences, with our inclusion of adults ≥60 years (those at risk for HF) and our cohorts being relatively fixed, rather than dynamic study samples. Our study used standardized criteria for inpatient and outpatient HF constant over the time in the cohort studies. Studies defining HF by hospitalization billing codes(21,23,24,27) may be subject to misclassification bias, and may underestimate HF events compared to physician-adjudicated data(11) and HF initially diagnosed in an outpatient setting.(20,24,28) Additionally, our greater geographic and/or racial-ethnic diversity may have contributed to these findings, highlighting the role for broader population samples to investigate disease trends. Examination of HF incidence by ethnic/racial groups is an area for future investigation.

Temporal trends and sex-differences in the incidence of HFREF vs. HFPEF, which have differential risk factors, have not been well described in broad population samples in the contemporary era. Our observed temporal decrease in HFREF incidence in men, contrasted with an increase in HFPEF incidence in both sexes, suggests a shift in the epidemiology of HF. Our findings are consistent with improvements in primary and secondary prevention and treatment of coronary artery disease, with a decline in ST-elevation myocardial infarctions, and increase in and prolonged survival of individuals with non-ST segment infarctions.(29,30) Sex differences in HFREF incidence after myocardial infarction may be explained by differences in and responses to treatment (invasive vs. conservative) strategies.(31) Our observed rise in HFPEF incidence in men is consistent with national inpatient data showing a rising prevalence of men with HFPEF over time.(32)

Risk of Mortality in HF 1990–2009

Despite major advances in HFREF therapeutics in the contemporary era, we observed similar mortality rates in HFREF and HFPEF, consistent with reports of HF mortality prior to 2000.(3,33) The risk of death from CVD- and non-CVD causes was not significantly improved, and the prevalence of MI and of sudden cardiac death were similar. That mortality was not improved over 1990 to 2009 is noteworthy, considering the increased use of evidence-based CVD and HF medications between decades in our cohort. However, our data also suggests that an equal to greater proportion of individuals with HF were not taking these medicines. Further, ACE inhibitors were administered in the minority of participants with HF, and prevalent use of this medication class was similar between decades. Our findings that blood pressure remained similar and suboptimal in both HFREF and HFPEF groups during both decades enforces the suggestion that individuals with HF were inadequately treated with guideline-directed medical therapy. In addition to the limited use of optimal medical therapy in the community, the lack of improvement in HF-associated mortality may reflect other factors, including non-cardiovascular morbidities not addressed by appropriate therapies, and/or differences in “real world” vs. trial HF patient characteristics, follow-up, and/or treatment. Notably, in HFPEF, non-CVD morbidity is significant and therapies prolonging survival remain elusive. In total, our results emphasize the need to improve prevention and treatment strategies for HF, particularly addressing HFREF in women and HFPEF in both men and women.

Funding: This study was supported by grants from the NIH N01-HC-25195, and HHSN268201500001I to the Framingham Heart Study/ Boston University School of Medicine and the CHS is supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. CWT was supported by K23 HL118529. JEH was supported by K23 HL116780.