The Association of Protein Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct clinical entities, yet there is scant evidence for associations of proteomic signatures with future development of HFpEF versus HFrEF. METHODS: We evaluated the association of 71 protein biomarkers with incident HFpEF versus HFrEF (left ventricular ejection fraction ≥ versus <50%) among Framingham Heart Study participants using multivariable Cox models. RESULTS: Among 7038 participants (mean age 49 years; 54% women), 5 biomarkers were associated with increased risk of incident HFpEF (false discovery rate q<0.05): NT-proBNP (N-terminal pro-B-type natriuretic peptide; hazard ratio [HR], 2.13; 95% CI, 1.52-2.99; P<0.001), growth differentiation factor-15 (HR, 1.67; 95% CI, 1.32-2.12; P<0.001), adrenomedullin (HR, 1.58; 95% CI, 1.23-2.04; P<0.001), uncarboxylated matrix Gla protein (HR, 1.55; 95% CI 1.23-1.95; P<0.001), and C-reactive protein (HR, 1.46; 95% CI, 1.17-1.83; P=0.001). Fourteen biomarkers were associated with incident HFrEF (multivariable P<0.001, q<0.05 for all). Of these, 3 biomarkers were associated with both HF subtypes (NT-proBNP, growth differentiation factor-15, and C-reactive protein). When compared directly, myeloperoxidase, resistin, and paraoxanase-1 were more strongly associated with HFrEF than HFpEF. CONCLUSIONS: We identified 5 protein biomarkers of new-onset HFpEF representing pathways of inflammation, cardiac stress, and vascular stiffness, which partly overlapped with HFrEF. We found 14 biomarkers associated with new-onset HFrEF, with some distinct associations including myeloperoxidase, resistin, and paraoxanase-1. Taken together, these findings provide insights into similarities and differences in the development of HF subtypes. REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT00005121; Unique identifier: NCT0005121.

Of Climate Change and Competing Risks.

Of Climate Change and Competing Risks This Stats, STAT! animated video explores the concept of competing risks - and discusses why it is so important for investigators to consider whether the occurrence of one event can prevent or change the likelihood of the occurrence of another.

Good Intentions to Treat.

Good Intentions to Treat This Stats, STAT! animated video explores common approaches to analyzing data from randomized controlled trials, including intention-to-treat, per-protocol, and as-treated analyses.

Association of Cardiometabolic Disease With Cancer in the Community.

Background: Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear. Objectives: The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer. Methods: FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models. Results: Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all). Conclusions: Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.

Cardiovascular disease related circulating biomarkers and cancer incidence and mortality: is there an association?

AIMS: Recent studies suggest an association between cardiovascular disease (CVD) and cancer incidence/mortality, but the pathophysiological mechanisms underlying these associations are unclear. We aimed to examine biomarkers previously associated with CVD and study their association with incident cancer and cancer-related death in a prospective cohort study. METHODS AND RESULTS: We used a proteomic platform to measure 71 cardiovascular biomarkers among 5032 participants in the Framingham Heart Study who were free of cancer at baseline. We used multivariable-adjusted Cox models to examine the association of circulating protein biomarkers with risk of cancer incidence and mortality. To account for multiple testing, we set a 2-sided false discovery rate <0.05. Growth differentiation factor-15 (also known as macrophage inhibitory cytokine-1) was associated with increased risk of incident cancer [hazards ratio (HR) per 1 standard deviation increment 1.31, 95% CI 1.17-1.47], incident gastrointestinal cancer (HR 1.85, 95% CI 1.37-2.50), incident colorectal cancer (HR 1.94, 95% CI 1.29-2.91), and cancer-related death (HR 2.15, 95% CI 1.72-2.70). Stromal cell-derived factor-1 showed an inverse association with cancer-related death (HR 0.75, 95% CI 0.65-0.86). Fibroblast growth factor-23 showed an association with colorectal cancer (HR 1.55, 95% CI 1.20-2.00), and granulin was associated with haematologic cancer (HR 1.61, 95% CI 1.30-1.99). Other circulating biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations with future cancer diagnosis. CONCLUSION: We observed several significant associations between circulating CVD biomarkers and cancer, supporting the idea that shared biological pathways underlie both diseases. Further investigations of specific mechanisms that lead to both CVD and cancer are warranted.

Threats to Blinding.

Blinding is a critical strategy used to limit certain types of bias in randomized controlled trials. This animated video explores the rationale and examines potential threats to keeping group allocation concealed - from study participants and investigators.

The Case of the Missing Data.

The Case of the Missing DataThis animated video explores how investigators approach missing data in clinical trials.

Subgroup Analyses: Subpar or Sublime?

Subgroup Analyses: Subpar or Sublime?This animated video explores some of the potential pitfalls of performing subgroup analyses in randomized controlled trials and explains how to approach potential findings with caution.

The Problem of Multiple Comparisons.

The Problem of Multiple Comparisons This animated video reviews the problem of multiple comparisons in research studies and explains how performing multiple statistical hypothesis tests can produce associations simply by chance.

Is Noninferior Not Inferior?

Is Noninferior Not Inferior? What is a non-inferiority trial margin? To answer this, ask whether you have ever weighed a tradeoff between the best version of something and an acceptable alternative. Restated, in a choice between two decisions, is one option not inferior to the other? Watch an animated video that explores the basis for non-inferiority trials, the meaning of non-inferiority margins, and the interpretation of a non-inferiority trial's results.

Should Combined Hormonal Contraception Be Stopped in the Perioperative Period?

Should Combined Hormonal Contraception Be Stopped in the Perioperative Period?A 34-year-old woman is scheduled to undergo surgery to manage a torn anterior cruciate ligament in her left knee. Her only medication is an estrogen- and progestin-containing oral contraceptive pill (OCP). Should she stop her combined oral contraception to reduce the risk of a postoperative blood clot?

Cardiovascular Risk Factors are Associated with Future Cancer.

BACKGROUND: The extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown. OBJECTIVES: We investigated the association of standard CVD risk factors, CVD biomarkers, preexisting CVD, and ideal CV health metrics with the development of future cancer. METHODS: We prospectively followed Framingham Heart Study and PREVEND participants free of cancer at baseline, and ascertained histology-proven cancer. We studied the association of baseline CV risk factors, 10-year atherosclerotic CVD risk score, established CVD biomarkers, prevalent CVD, and AHA Life's Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates. RESULTS: Among 20,305 participants (mean age 50 ± 14 years, 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 (13.3-15.0) surveillance years. Traditional CVD risk factors including age, sex, and smoking status were independently associated with cancer (P <0.001 for all). Estimated 10-year atherosclerotic CVD risk was also associated with future cancer (HR 1.16 per 5% increase in risk, 95% CI 1.14-1.17, P<0.001). We found that natriuretic peptides (NP) (tertile 3 vs 1: HR 1.40, 95% CI 1.03-1.91, p=0.035) was associated with incident cancer, but not high sensitivity troponin (hs-cTn) (p=0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with lower future cancer risk (HR 0.95 per 1-point increase in AHA health score, 95% CI 0.92-0.99, p=0.009). CONCLUSIONS: CVD risk as captured by traditional CVD risk factors, 10-year atherosclerotic CVD risk score, and NP concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a reduced risk of future cancer. Our data suggest that the association between CVD and future cancer is attributable to shared risk factors.