Increased cardiac workload by closure of the ductus arteriosus leads to hypertrophy and apoptosis rather than to hyperplasia in the late fetal period

Abstract

It is generally thought that adult mammalian cardiomyocytes compensate for an increased workload by hypertrophy, whereas fetal myocardium grows by cellular proliferation. We analyzed the response of late-fetal rat hearts upon an increased workload imposed by premature constriction of the ductus arteriosus with indomethacin. Initially the fetal heart responds by proliferative growth, as both wet weight and labeling index (bromodeoxyuridine incorporation) of the ventricles increased, whereas neither a change in the fibroblast fraction, ploidy and nucleation in the ventricles is observed. However, this hyperplastic growth is abrogated by a subsequent burst in apoptosis and followed by a hypertrophic response as based on a decrease in DNA and increase in both RNA and protein concentration. This hypertrophic growth was accompanied by a 1.4-fold increase in the volume of the cardiomyocytes. Changes in the molecular phenotype characteristic of pressure-overload hypertrophic growth accompany the process. Thus, the levels of expression of beta-myosin heavy chain and atrial natriuretic factor mRNA increased, of sarcoplasmic/endoplasmic reticulum ATPase (SERCA2) mRNA decreased, and of alpha-myosin heavy chain, phospholamban, and calsequestrin mRNA did not change. In situ hybridization showed that the pattern of mRNA expression changed first in the right ventricular wall and subsequently in the left ventricular free wall as well. It is concluded that pressure-overload imposed on the late-fetal heart induces limited proliferative growth complemented by extensive hypertrophic growth.

Neonatal cardiomyocyte ploidy reveals critical windows of heart development

“…This result is in good agreement with the data obtained with late-fetal rat myocardium after ductus arteriosus constriction [54].…”

Intrauterine Closure of the Ductus Arteriosus: Implications for the Neonatologist

“…A fetus affected by intrauterine closure of the DA may present with various signs of cardiac failure: dilated right ventricle, tricuspid regurgitation, abnormal venous Doppler, marked hypertrophy of the right ventricle and the interventricular septum, and increased pulmonary blood flow. [19][20][21] Doppler echocardiography is useful in assessing flow velocity in the fetal ductus and in detecting DA constriction. Failure to identify normal ductal diastolic runoff from the pulmo-nary artery to the descending aorta in a fetus in association with right ventricular failure and tricuspid valve regurgitation signify complete ductal occlusion.…”

Brazilian Fetal Cardiology Guidelines - 2019

“…78,88 With the increased afterload secondary to ductal constriction, the heart shows symptoms of growth in earlier stages, hypertrophic response, with hyperplasia (substituted by apoptosis), increased right chamber proportions, increased pulmonary artery to aorta ratio, and interventricular septum bulging into the left ventricle. 89,90 It is important to highlight that the diagnosis of ductal constriction and the evaluation of its severity cannot be established solely in terms of categorical variables of the "yes/no" sort, but are based rather on continuous variables, with a spectrum of circulation compromise (mild, moderate, or severe) which has been summarized in Table 6.1.…”