Heart Failure With Normal Ejection Fraction

A Growing Pandemic

Satnam Singh; Michael Frenneaux


Future Cardiol. 2012;8(3):383-392. 

In This Article

Pathophysiology of HFNEF

Structural Model

Increased myocardial stiffness is a major cause of LV diastolic dysfunction. Myocardial stiffness in turn is regulated by extracellular matrix (mainly collagen), the cardiomyocytes and matricellular proteins. Of the various types, dysregulation of collagen type I synthesis and degradation leads to increased myocardial stiffness. A giant sarcomere protein titin plays a role in determining the stiffness of myocardium.[17]

Titin is expressed in myocardium in two isoforms: N2B (the more rigid form) and N2BA (more compliant). The alterations in the relative expression of the two titin isoforms or alterations in their state of phosphorylation have been implicated in the pathophysiology of HFNEF. Evidence shows that a relative increase in the expression of the more rigid titin isoform, N2B is related to HFNEF. In a healthy heart the normal N2BA:N2B ratio is approximately 30:70, but in patients with HFNEF, this ratio is reduced to 17:83. Like other cytoskeletal proteins, titin is also subject to phosphorylation by PKA and PKG, leading to a downward shift of resting length relationship causing enhanced compliance. Impairment of this phosphorylation of titin along with troponin I appear to contribute to abnormal diastolic dysfunction in HFNEF. The role of matricellular proteins remains unexplored in HFNEF.

Myocardial fibrosis is a key pathological process in LVH and contributes to abnormalities of cardiac function, of coronary reserve and of electrical activity. It is a complex process reflecting the loss of balance between stimulatory and inhibitory factors acting on the turnover of fibrillar collagen.[18] Chronic pressure overload stimulates both procollagen gene expression and collagen protein synthesis leading to excessive collagen deposition and fibrosis. Evidence supports the central role of angiotensin II responsible for myocardial fibrosis. It induces fibroblast stimulation, proliferation, alteration of fibrillar collagen turnover and stimulation of aldosterone, leading to accumulation of excessive collagen and fibrosis.[19] Type 1 collagen is the main constituent of extracellular matrix, which together with LVH contributes to myocardial stiffness.[20,21]

Collagen accumulation in myocardium, collagen cross-linking and collagen phenotype shift appears to play a major role in myocardial stiffness and hence HFNEF with small contributions from LVH and LV relaxation abnormalities.[22–25] It is the result of chronic arterial hypertension that contributes to abnormalities of cardiac function. Patients with hypertension have increased interstitial collagen deposition along with fibrosis leading to LV stiffness.[26]

Metabolic Model

Impaired LV relaxation is often observed at rest. More importantly, the rate of LV active relaxation normally increases on exercise and this is crucial for adequate filling of the LV at high heart rates. It is due to sympathetic activation with PKA-mediated phosphorylation of key proteins involved in calcium handling and sarcomere cross-link breaking and is highly energy dependent.[27] Patients with HFNEF have cardiac energy impairment and accordingly instead of LV active relaxation becoming more rapid during exercise it becomes paradoxically slower and this almost certainly plays a crucial role in the exercise limitation that characterizes the disorder.[28]


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