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Backgrounds and Aims: Simple, long-term epidemiological observations allowed to identify a heterogeneous group of heart diseases manifested only as heart failure, arrhythmia and blocks in the absence of typical coronary syndromes, that we arbitrarily called initially atypical Coronary Heart Disease (CHD) and then Heart Disease of Uncertain Etiology (HDUE) in 12 published investigations.

Methods and Results: This group of heart diseases covered about 20% of all CVD mortality and about 10% of all-cause mortality in population cohorts close to extinction and compared with typical CHD was characterized by a strong association with age and the absence or an inverse association with serum cholesterol, dietary habits and physical activity. Moreover, HDUE appeared at an older age and had a higher age at death. Blood pressure and smoking habits (the latter with some uncertainties) were directly associated with the disease. Old pathology findings had already segregated the large myocardial scars due to gross atheroma of coronary arteries from small multiple sclerotic/fibrotic scars that seem independent and unrelated to coronary atheroma.

Conclusion: Etiology of HDUE, although probably multiple, is still vague and elusive, and the Literature was little informative about its relative frequency and possible causality. Future investigations might be stimulated by this review. To segregate HDUE from CHD should be important to correctly assess relationships among multiple risk factors and differential or condensed outcomes.