# Sex Differences in the Relationship between New York Heart Association Functional Classification and Survival in Cardiovascular Disease Patients: A Mediation Analysis of Exercise Capacity with Regular Care Data

## TL;DR

This study shows that the relationship between heart function classification and survival differs between men and women, with exercise capacity playing a key role.

## Contribution

The study identifies sex-specific mediation effects of exercise capacity on the NYHA classification and survival link.

## Key findings

- In men, higher NYHA classes correlated with increased mortality in a dose-response pattern.
- In women, NYHA classes II and III/IV showed similar mortality risks.
- Proportional workload during stress tests explained more of the survival risk in women than in men.

## Abstract

The New York Heart Association (NYHA) functional class has
extensively been used for risk stratification in patients suspected of heart
failure, although its prognostic value differs between sexes and disease
entities. Functional exercise capacity might explain the association between NYHA
functional class and survival, and can serve as an objective proxy for the
subjective nature of the NYHA classification. Therefore, we assessed whether
sex-differences in exercise capacity explain the association between NYHA
functional class and survival in patients suspected of cardiovascular disease.

Electronic health record data from 7259 patients with
cardiovascular symptoms, a documented NYHA functional class and cardiac stress
electrocardiogram (ECG), was analysed. Follow-up for all-cause mortality was
obtained through linkage with Statistics Netherlands. A sex-stratified mediation
analysis was performed to assess to what extent the proportional heart rate and
-workload during ECG stress testing explain the association between NYHA
functional class and survival.

In men, increments in NYHA
functional class were related to higher all-cause mortality in a dose-response
manner (NYHA II vs III/IV: hazard ratio [HR] 1.59 vs 3.64, referenced to NYHA I),
whilst in women those classified as NYHA functional class II and III/IV had a
similar higher mortality risk (HR 1.49 vs 1.41). Sex-stratified mediation
analysis showed that the association between NYHA and survival was mostly
explained by proportional workload during stress ECG (men vs women: 22.9%, 95%
CI: 18.9%–27.3% vs 40.3%, 95% CI: 28.5%–68.6%) and less so by
proportional heart rate (men vs women: 2.5%, 95% CI: 1.3%–4.3% vs 8.0%,
95% CI: 4.1%–18.1%). Post-hoc analysis showed that NYHA classification
explained a minor proportion of the association between proportional workload and
all-cause mortality (men vs women: 15.1%, 95% CI: 12.0%–18.3% vs 4.4%, 95%
CI: 1.5%–7.4%).

This study showed a significant
mediation in both sexes on the association between NYHA functional class and
all-cause mortality by proportional workload, but the effect explained by NYHA
classification on the association between survival and proportional workload is
small. This implies that NYHA classification is not a sole representation of a
patient’s functional capacity, but might also incude other aspects of the
patient’s overall health status.