The role of diagnostic “red flags” in hypertrophic cardiomyopathy (HCM) is gaining prominence as a strategy to guide personalized management. A multinational cohort study, published in the European Heart Journal, evaluated the prevalence and clinical significance of predefined red flags across diverse HCM phenotypes. The study analyzed 818 patients referred to four European centers, assessing diagnostic markers from clinical history, examination, electrocardiography, echocardiography, and laboratory testing.

Across the cohort, 2,979 red flags were identified, with 34% detectable through clinical history and physical examination alone, suggesting strong diagnostic potential even in generalist settings. Genetic testing revealed that 39% of patients carried pathogenic sarcomere variants, while 29% had TTR and GLA mutations, 19% a syndromic cause, and 13% no identifiable cause. Non-sarcomeric patients were often diagnosed at younger than 20 or older than 60 years. Syndromic causes such as Rasopathies, metabolic, and mitochondrial disorders typically present in childhood, while Danon disease, Friedreich’s ataxia, Noonan syndrome, and PRKAG2 cardiomyopathy emerge during adolescence.

Non-cardiac red flags predominated in non-sarcomeric etiologies, whereas electrocardiographic and echocardiographic markers dominated in sarcomeric HCM. The findings highlight that early recognition of red flags, particularly in primary care, may significantly improve diagnostic yield and optimize resource use.