Consistent with the understanding of the comorbidity-infl ammation relationship, concomitant diseases and especially metabolic comorbidities are thought to stimulate the development and severity of heart failure with preserved ejection fraction through a cascade of mechanisms supporting systemic tissue infl ammation leading to myocardial fi brosis. Recently, new experimental and clinical evidence has emerged that enhances validity and verifi es the infl ammatory-profi brotic paradigm. This evidence consists of: (1) myocardial infi ltration with immunocompetent cells not only due to metabolic load caused by obesity but also due to arterial hypertension-induced haemodynamic loading of extracellular matrix components (such as basal laminatin interacting with basal laminate); (2) expression in cardiomyocytes of inducible nitric oxide synthetase under the infl uence of circulating proinfl ammatory cytokines, which leads to accumulation of degraded proteins in the myocardium due to an unfolded protein response; (3) defi ning phenogroups of patients with heart failure with preserved ejection fraction with a distinct infl ammatory and profi brotic component by machining algorithms; (4) direct association. in mediation analysis between comorbidities, infl ammatory biomarkers and impaired myocardial structure and function with endothelial expression of adhesion molecules already accumulated in early preclinical heart failure with preserved ejection fraction (CH stage A, B). This new evidence paves the way for future treatment of heart failure with a conserved ejection fraction with biologics directed against 1) infl ammatory cytokines, 2) stimulating the development of a complete protein response and non-accumulation of protein in the chiocardia by phosphodiesterase inhibitors 1) the rigidity of titin by natriuretic peptide – the particular guanylyl cyclase – PDE9 (phosphodiesterase 9) and 4) molecular and cellular regulatory mechanisms that control myocardial fi brosis.