Miller PE; University School of Medicine, Boston, MA, USA
Gajjar P; Mitchell GF; Khan SS; Vasan RS; Larson MG; Lewis GD;
Shah RV; Nayor M

ESC heart failure. 11(5):3279-3289, 2024 Oct.

AIMS: New tools are needed to identify heart failure (HF) risk earlier in
its course. We evaluated the association of multidimensional
cardiopulmonary exercise testing (CPET) phenotypes with subclinical risk
markers and predicted long-term HF risk in a large community-based cohort.

METHODS AND RESULTS: We studied 2532 Framingham Heart Study participants
[age 53 +/- 9 years, 52% women, body mass index (BMI) 28.0 +/- 5.3 kg/m2,
peak oxygen uptake (VO2) 21.1 +/- 5.9 kg/m2 in women, 26.4 +/- 6.7 kg/m2
in men] who underwent maximum effort CPET and were not taking
atrioventricular nodal blocking agents. Higher peak VO2 was associated
with a lower estimated HF risk score (Spearman correlation r: -0.60 in men
and -0.55 in women, P < 0.0001), with an observed overlap of estimated
risk across peak VO2 categories. Hierarchical clustering of 26 separate
CPET phenotypes (values residualized on age, sex, and BMI to provide
uniformity across these variables) identified three clusters with distinct
exercise physiologies: Cluster 1-impaired oxygen kinetics; Cluster
2-impaired vascular; and Cluster 3-favourable exercise response. These
clusters were similar in age, sex distribution, and BMI but displayed
distinct associations with relevant subclinical phenotypes [Cluster
1-higher subcutaneous and visceral fat and lower pulmonary function;
Cluster 2-higher carotid-femoral pulse wave velocity (CFPWV); and Cluster
3-lower CFPWV, C-reactive protein, fat volumes, and higher lung function;
all false discovery rate < 5%]. Cluster membership provided incremental
variance explained (adjusted R2 increment of 0.10 in women and men, P <
0.0001 for both) when compared with peak VO2 alone in association with
predicted HF risk.

CONCLUSIONS: Integrated CPET response patterns identify physiologically
relevant profiles with distinct associations to subclinical phenotypes
that are largely independent of standard risk factor-based assessment,
which may suggest alternate pathways for prevention.