The pathophysiology of diastolic heart failure. Mechanisms of diastolic dysfunction from the sarcomere through to the intact heart coupled with the vasculature. At the level of the myofilament, abnormal stiffness and relaxation can occur by modifications of proteins within the contractile thick and thin filaments, myosin-binding protein C, and the linkage protein titin. Changes in the PEVK region of titin among its isoforms can confer differential stiffness and elastic recoil to the myocardium. At the myocyte level, calcium signalling and interaction with myofilaments play an important role. Expression and post-translation modifications of the sarcoplasmic reticulum calcium release channel, Ca²⁺ uptake proteins (PLB, SERCA), sarcolemma exchanger, and ion pumps (Na⁺,K⁺-ATPase) by kinases all participate in this interaction. At the next level of integration, diastolic properties are coupled with an EC matrix that surrounds each myocyte and forms bundles among muscle fibres. The scanning electron micrograph (left) shows the connective tissue skeleton from a human heart, with perimysial fibres (P) enveloping groups of myocytes, smaller endomysial fibres supporting and connecting individual cells, and endomysial weave (W) enveloping individual myocytes, with cells linked to adjacent cells by lateral struts (S). Collagen is also post-translationally crosslinked to alter its properties (including generation of advanced glycation crosslinks) from protein/glucose interaction. At the integrated organ level, properties of the heart are impacted by the vascular loads imposed, by geometric factors, and external constraints (pericardium/ right heart). Measured DPVRs shifted upward in parallel (a vs c, top right) more commonly reflect such extrinsic influences, whereas intrinsic stiffness appears as a steeper relation (a vs b). AGE, advanced glycation cross-links; MyBPC, myosin-binding protein C; NCX, sarcolemma exchanger; NKATP, Na⁺,K⁺-ATPase; P, perimysial fibres; RyR, reticulum calcium release channel; S, lateral struts; W, endomysial weave.