Transition model of “systolic heart failure”

The increase in cardiac chamber size in heart failure is largely a structural problem, and a low LV ejection fraction is to some extent obligated by the increase in LV chamber size.For example, maintenance of a normal ejection fraction of 62% in a left ventricle with an end-diastolic volume of 350 to 400 mL would deliver an enormous stroke volume, perhaps one that might even cause disruption of the normal homeostatic coupling between the heart and the periphery. In a sense, the low LV ejection fraction may be adaptive in the context of such a large LV end-diastolic volume, thus protecting the peripheral circulation from an unusually high pulse pressure. One could argue that a large chamber volume “obligates” a reduced ejection fraction to maintain normal homeostatic coupling.

Today’s working model of heart failure represents a probable transition from an index event of a susceptible individual, beginning with a genetic mutation or acute injury due to myocardial infarction or inflammation, passing through a progressive remodeling phase, and finally arriving at the clinical syndrome of heart failure(table below )  The known responses to acute or chronic myocardial injury include myocyte growth with deposition and replacement of interstitial collagen. Additional factors that probably contribute to LV remodeling include myocyte slippage, perhaps caused by dissolution of collagen struts that normally hold the cells together, and increased cell loss caused by the process of apoptosis. 

Many of the processes are present in all patients, but the quantitative contributions of myocyte slippage and apoptosis to the cardiac remodeling process are not entirely clear. Moreover, there are some who believe that there is an overall increase in the number of cardiac myocytes during the development of hypertrophy and remodeling of heart failure,although the classic teaching up to now has been that cardiac cells, being highly differentiated, are unlikely to enter into the cell cycle. Eventually, the remodeling process and its hemodynamic burden, aggravated by activation of multiple neurohormones and cytokines, causes a further change in the size and the shape of the heart, leading to cardiomegaly and reduced LV systolic function.^[23] The process is extraordinarily complex, with activation of multiple, redundant signaling pathways and crosstalk between signal transduction pathways. There is a highly complex interaction between mechanical signals, such as stretch of cell membranes, and various neurohormones and cytokines, making a single “silver bullet” therapy an unrealistic concept.
This model states that there is an index event, such as a myocardial injury or expression of mutation. This progresses to a remodeling phase and ultimately to the full expression of the clinical syndrome of heart failure. There is plasticity of the phenotype, with variation in pace of development of progression.
Referenced ;

1-Francis G.S.: Changing the remodeling process in heart failure: basic mechanisms and laboratory results. Curr Opin Cardiol  1998; 13:156-161.

2-Francis G.S., McDonald K.M.: Left ventricular hypertrophy: an initial response to myocardial injury. Am J Cardiol  1992; 69:3G-7G.discussion 7G-9G

3-Kajstura J., Leri A., Finato N., et al: Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A  1998; 95:8801-8805.

4-Beltrami A.P., Urbanek K., Kajstura J., et al: Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med  2001; 344:1750-1757.
5-Soonpaa M.H., Field L.J.: Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res  1998; 83:15-26.

6-Cohn J.N.: Structural basis for heart failure. Ventricular remodeling and its pharmacological inhibition. Circulation  1995; 91:2504-2507.