Supplementary file 1_Environmental cold exposure and cardiovascular mortality: biological mechanisms, regional heterogeneity, and public health implications.docx

Among 26 epidemiological studies contributing to the regional synthesis, substantial heterogeneity was observed in study design, population coverage, temperature metrics, cold definitions, lag structures, covariate adjustment, analytical approaches, outcomes, and effect measures. Methodological credibility was considered qualitatively rather than through a formal risk-of-bias score, with greater interpretive weight given to large multi-location, nationwide, or within-country studies applying standardized or internally consistent analytical frameworks.

Illustrative reported estimates included approximately 6.3% of cardiovascular deaths attributable to temperatures below the county-specific minimum mortality temperature in a US analysis, 11.4% (95% CI 6.0–15.4%; lag 0–14 days) attributable to temperatures below the city-specific optimum temperature in a seven-city Norwegian analysis, and a cold-wave-related cardiovascular mortality RR of 1.076 (95% CI 1.061–1.090; lag 0–3 days) in a nationwide Thai study.

Because exposure definitions, lag structures, analytical approaches, outcomes, and effect measures differed substantially among studies, no consistent quantitative gradient in vulnerability by climatic setting, latitude, or socioeconomic context could be established. The qualitative evidence suggests that regional patterns may reflect a combination of climatic conditions, biological susceptibility, behavioral responses, socioeconomic circumstances, housing and heating conditions, healthcare capacity, population-level adaptive capacity, and methodological differences.

Their relative contributions cannot be determined from the available evidence, and evidence from many warm-climate and lower-resource settings remains limited.</p>