Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community

Abstract

Background: Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of noncardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and noncardiac organ dysfunction would accelerate the manifestation of HF.

Methods and results: We studied 1038 participants of the Framingham Heart Study original cohort (mean age, 76±5 years; 39% men) with routine assessment of left ventricular systolic and diastolic function. Major noncardiac organ systems were assessed with the use of serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second to forced vital capacity (FEV(1):FVC ratio; pulmonary), hemoglobin concentration (hematologic/oxygen-carrying capacity), and white blood cell count (systemic inflammation). On follow-up (mean, 11 years), there were 248 incident HF events (146 in women). After adjustment for established HF risk factors, antecedent left ventricular systolic dysfunction (hazard ratio, 2.33; 95% confidence interval, 1.43 to 3.78) and diastolic dysfunction (hazard ratio, 1.32; 95% confidence interval, 1.01 to 1.71) were associated with increased HF risk. After adjustment for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios, and lower hemoglobin concentrations were associated with increased HF risk (all P<0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each noncardiac organ system was associated with a 30% increased risk of HF (P=0.013).

Conclusions: Antecedent cardiac dysfunction and noncardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of noncardiac factors in its occurrence.

Figure 1. Association of measures of major non-cardiac organ system function with risk of incident heart failure

Generalized additive models with penalized splines were used to assess the association of multivariable-adjusted hazards ratio for heart failure with (A) serum creatinine concentration, (B) ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1:FVC ratio) and (C) hemoglobin concentration. Lines indicate means (solid) and 95% confidence intervals (dotted). *Y-axes represent multivariable-adjusted Ln (hazards ratio). To obtain serum creatinine concentration in μmol/l, multiply values in mg/dl by 88.4.

Figure 1. Association of measures of major non-cardiac organ system function with risk of incident heart failure

Generalized additive models with penalized splines were used to assess the association of multivariable-adjusted hazards ratio for heart failure with (A) serum creatinine concentration, (B) ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1:FVC ratio) and (C) hemoglobin concentration. Lines indicate means (solid) and 95% confidence intervals (dotted). *Y-axes represent multivariable-adjusted Ln (hazards ratio). To obtain serum creatinine concentration in μmol/l, multiply values in mg/dl by 88.4.

Figure 1. Association of measures of major non-cardiac organ system function with risk of incident heart failure

Generalized additive models with penalized splines were used to assess the association of multivariable-adjusted hazards ratio for heart failure with (A) serum creatinine concentration, (B) ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1:FVC ratio) and (C) hemoglobin concentration. Lines indicate means (solid) and 95% confidence intervals (dotted). *Y-axes represent multivariable-adjusted Ln (hazards ratio). To obtain serum creatinine concentration in μmol/l, multiply values in mg/dl by 88.4.

Figure 2. Cumulative incidence of incident heart failure according to non-cardiac major organ system dysfunction risk score

The non-cardiac organ system dysfunction risk score awarded 1 point for the presence of each of the following (range 0-3): serum creatinine >1.05 mg/dl (92.8 μmol/l), ratio of forced expiratory volume in 1 second to forced expiratory volume <91% predicted, hemoglobin concentration <13 g/dl. Increasing non-cardiac risk score at baseline was associated with increasing risk of incident heart failure (HF) in our community-based sample (log rank P value = 0.013).