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BACKGROUND AND AIMS: The relationship between uncommon phenotypes, such as metabolically healthy obesity and normal weight with metabolic syndrome (MetS), and cardiovascular disease (CVD) risk, remains unclear. We investigated how different combinations of body mass index (BMI) and MetS are associated with overall and specific CVDs and how the number of MetS components influences CVD risk in individuals with obesity.

METHODS AND RESULTS: We performed separate analyses and a meta-analysis of 36,233 individuals from four Swedish cohorts to assess the risk of incident CVDs across BMI/MetS combinations (normal-weight, overweight or obese/MetS yes or no). Participants were followed for CVDs and death through linkage to the Swedish National Registers. Compared to normal weight without MetS, overweight and obesity without MetS had most pronounced association with the risk of heart failure [multivariable hazard ratios, HR (95 % CI) = 1.37 (1.16-1.63) and 1.85 (1.37-2.48), respectively, p < 0.001]. In obese individuals, the risk of incident CVD (composite endpoint) increased with an increasing number of MetS components, but this relationship was not statistically significant in obese participants without additional MetS components, likely due to the small at-risk group. Normal-weight individuals with MetS had an increased risk of myocardial infarction [HR (95 % CI) 2.0 (1.51-2.64)], p < 0.001, and stroke [HR (95 % CI) 1.63 (1.17-2.28), p = 0.004].

CONCLUSIONS: Overweight and obesity without MetS showed a greater impact on the risk of heart failure, whereas normal-weight individuals with MetS had a higher risk of myocardial infarction and stroke. In obese individuals, CVD risk increased as the number of MetS components increased.