Integrating body mass index and waist-to-hip ratio identifies the 'lemon-on-sticks' phenotype as a high-risk subgroup in heart failure
C C S Van Der Hoef, J M Ter Maaten, W Ouwerkerk, C C Lang, A A VoorsAbstract
Introduction
In patients with heart failure, higher body mass index (BMI) is paradoxically associated with better outcomes and lower natriuretic peptide levels, while emerging data suggest this relationship may differ for waist-to-hip ratio (WHR). To better understand this dissociation, we studied and integrated clinical and biochemical phenotypes according to BMI and WHR in patients with heart failure.
Methods
We studied 1467 patients with heart failure, categorized into high and low BMI and WHR using median cut-offs (BMI 28.1 kg/m²; WHR 0.97), and subsequently subdivided into four phenotypic BMI/WHR quadrants: low BMI/high WHR phenotype (or ‘lemon-on-sticks’), high BMI/low WHR phenotype (or ‘general adiposity’), and the two concordant BMI/WHR (low/low and high/high) phenotypes. Clinical characteristics and serum biomarkers reflecting congestion, metabolic risk, inflammation, and adiposity were compared across quadrants. Associations between N-terminal pro–B-type natriuretic peptide (NT-proBNP) and BMI or WHR were assessed in the total cohort. Survival analyses evaluated all-cause mortality across the quadrants.
Results
Patients with a low BMI were significantly older than those with a high BMI, irrespective of WHR. High WHR was associated with male sex and greater functional limitation. NT-proBNP levels were consistently lower in patients with higher BMI (p<0.001), whereas WHR showed no meaningful association with NT-proBNP (p=0.330). Patients with the combination of a low BMI and high WHR (the ‘lemon-on-sticks’ phenotype) showed the strongest signs of congestion and the highest plasma concentrations of NT-proBNP, Growth Differentiation Factor 15 (GDF-15) and (Cancer Antigen 125) CA-125, along with a predominantly inflammatory profile, and had the worst clinical outcomes (age- and sex-adjusted hazard ratio ~2.2 compared with patients with a high BMI and low WHR). The inverse phenotype of ‘general adiposity’ defined by a high BMI and low WHR had the lowest levels of NT-proBNP, GDF-15 and CA-125. This phenotype was characterized by higher leptin levels reflecting overall adiposity rather than inflammation and had the best clinical outcome.
Conclusion
Integrated phenotypes based on BMI and WHR in heart failure patients show marked differences in clinical profile and prognosis. The ‘lemon-on-sticks’ phenotype represents a high-risk subgroup with severe disease and the worst clinical outcome, whereas those with ‘general adiposity’ show the lowest disease severity and best clinical outcome.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.