Myocardial factor revisited: The importance of myocardial fibrosis in adults with congenital heart disease

Abstract

Pioneers in congenital heart surgery observed that exercise capacity did not return to normal levels despite successful surgical repair, leading some to cite a "myocardial factor" playing a role. They conjectured that residual alterations in myocardial function would be significant for patients' long-term outlook. In fulfillment of their early observations, today's adult congenital heart disease (ACHD) population shows well-recognized features of heart failure, even among patients without clear residual anatomic or hemodynamic abnormalities, demonstrating the vital role of the myocardium in their morbidity and mortality. Whereas the 'myocardial factor' was an elusive concept in the early history of congenital heart care, we now have imaging techniques to detect and quantify one such factor--myocardial fibrosis. Understanding the importance of myocardial fibrosis as a final common pathway in a variety of congenital lesions provides a framework for both the study and treatment of clinical heart failure in this context. While typical heart failure pharmacology should reduce or attenuate fibrogenesis, efforts to show meaningful improvements with standard pharmacotherapy in ACHD repeatedly fall short. This paper considers the importance of myocardial fibrosis and function, the current body of evidence for myocardial fibrosis in ACHD, and its implications for research and treatment.

Keywords: Cardiac magnetic resonance; Congenital; Heart defects; Heart failure; Myocardial fibrosis.

Figure 1

Scatterplot of ejection fraction for the left (LVEF) and right (RVEF) ventricles in consecutive patients with congenital heart disease referred for cardiac magnetic resonance. The light gray bar represents those with mild systolic dysfunction, and the dark gray those with moderate/severe systolic dysfunction. Percentages of patients have reduced ejection fraction are given. Systolic dysfunction spans the spectrum of age.

Figure 2

Simplified schema of heart failure. Primary insults lead to various signaling pathways involving common cytokines and neurohormonal activators that in term signal enzymatic reactions. These enzymatic reactions, namely performed by myofibroblasts, lead eventually to myocardial fibrosis. The presence of fibrosis causes myocardial diastolic and systolic function, as well as arrhythmia, all of which are clinical features of heart failure. While there are multiple additional activities involved in the process of heart failure, this demonstrates the central role of myocardial fibrosis between preclinical events and clinical manifestations.

Figure 3

Hematoxylin and eosin stain (400× magnification) of a right ventricular myocardial sample from a single patient with tetralogy of Fallot. Myocardial fibrosis in some areas is patchy “replacement” fibrosis with dense extracelullar material (left) as may be viewed by late gadolinium enhancement. Other areas show much more microscopic, diffuse fibrosis (right), more common in congenital heart disease, which is detectable by methods that measure the extraceullular volume fraction. Both types of fibrosis are present in the same patient (Courtesy of Dr. Henryk Kafka and Mary Shepperd, Royal Brompton Hospital).

Figure 4

Examples of extracellular volume (ECV) assessment in two patients with tetralogy of Fallot. A T1 inversion recovery sequence through the mid myocardium is obtained before and after administration of gadolinium contrast. Phases 3–10 of images taken 15 minutes after gadolinium are shown (top). These images are used to plot a time signal intensity curve from which exponential fitting is used to define T1 times (left graph). The reciprocal of each T1 time (R1) before and after gadolinium (three time points after injection are shown here) is plotted against corresponding times for the blood pool in the left ventricle (right graph). The linear slope of this relationship is used to quantify ECV. Compared to patient 2, patient 1 reaches a low signal (dark myocardium) sooner (top bar), consistent with a shorter T₁ time (left graph), and a steeper slope (right graph), coinciding with a higher ECV.