Patients with heart failure with preserved ejection fraction (HFpEF) constitute a heterogenous group with significant differences in clinical phenotypes, comorbidities and profiles between men and women. Diastolic dysfunction plays a key role in HFpEF; both left ventricular relaxation disturbances and the increase of passive ventricular stiffness may result in left ventricular filling abnormalities at rest and during exercise. However additional factors such as increased arterial stiffness and abnormal ventricular-arterial coupling, chronotropic incompetency, blunted arterial vasodilator’s reactivity and pulmonary hypertension have been considered in the pathophysiology of HFpEF recently. Novel paradigms for HFpEF assume that myocardial remodeling and diastolic dysfunction are the result of the cumulation of comorbidities that induce systemic inflammation with coronary endothelial dysfunction and reduced activity of protein kinase G. Inflammatory process with dysfunction of endothelium and decreased bioavailability of nitric oxide, resulting in structural and functional myocardial changes, constitute a mechanistic link between comorbidities and evolution and progression of HFpEF. The paper presents novel paradigms for HFpEF with the heterogeneity of clinical phenotypes in subjects with this feature of hearl failure.