Over the last 35 years, there has been an increased emphasis on viewing heart failure as a progressive process, and with this viewpoint has come a shift towards a neurohormonal model of heart failure. In this model, heart failure can be understood as an evolving disorder that takes place after an index event. That initial insult can be something acute, like a myocardial infarction, or hereditary, like genetic cardiomyopathies. Regardless of the event itself, there is a shared common pathway in which myocytes are damaged, the ability of the myocardium to generate force is disrupted, and there is an ensuing decline in pump function.
While patients will generally remain either asymptomatic, or minimally symptomatic in the time period immediately following the index event, that is in part because of a series of compensatory mechanisms employed by the body, aimed at preserving left ventricular function.
These mechanisms are thought to include “early activation of the adrenergic nervous system” to preserve cardiac output and “activation of a family of vasodilatory molecules, including natriuretic peptides, prostaglandins, and nitric oxide” to counteract the vasoconstriction promoted by excessive activation of the adrenergic system and the renin-angiotensin-aldosterone system (RAAS).
This neurohormonal model of heart failure postulates that even before the clinical syndrome of heart failure is phenotypically present, there is a series of abnormally expressed biologically active molecules, some of which in time have a profoundly negative impact on the heart and circulation and are therefore potentially promising areas for targeted medical therapies.
Heart failure as a progressive process: a neurohormonal model.
The neurohormonal model of heart failure that emphasizes targeting the adrenergic and RAAS to slow the progression of disease is well established.
Yet, it has been difficult to determine the proper use of adult heart failure medications in the pediatric population. The therapies which have been shown to be efficacious in adults do not have great evidence supporting their use in children. There are certainly several reasons this may be the case. Negative studies do not necessarily mean that the drugs do not work, but may in fact be explained by the challenges of study design and implementation.
Prospective pediatric trials are nearly universally underpowered to detect survival differences in pediatric heart failure. Additional challenges exist with the lack of pharmacokinetic and pharmacodynamic data for many medications.
However, it is also worth considering whether the neurohormonal model is applicable to children with heart failure in the same manner as adults with heart failure. The pediatric and adult heart failure populations are in fact quite different with respect to underlying diseases and demonstrate different gene expression and molecular characteristics
Hence, improved understanding of a pediatric specific model of heart failure would lead to new targets of therapy.
Rossano JW, Shaddy RE. Heart failure in children: etiology and treatment. J Pediatr 2014;165:228–33. http://dx.doi.org/10.1016/j.jpeds.2014.04.055.
Rossano JW, Shaddy RE. Update on pharmacological heart failure therapies in children: do adult medications work in children and if not, why not? Circulation 2014;129:607–12. http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003615.
Yellon L, Opie D, editors. Cardiology at the limits IV. London: University of Cape Town and University College, London; 2001. editors.
Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468–75. http://dx.doi.org/10.1056/NEJM199111213252103.