Background: The clinical symptoms of heart failure in infants with left-to-right shunts are thought to be explained by well-known hemodynamic disturbances such as pulmonary hypertension and overcirculation, but previous studies have not, thus far, found the expected correlations with hemodynamic and clinical parameters. Based on the neurohormonal model of heart failure, we hypothesised that the clinical symptoms of infants with left-to-right shunts are also related to neurohormonal disorders. Methods: We compared various neurohormonal and hemodynamic parameters measured invasively in 70 infants with left-to-right shunts to the respiratory rate and gain in weight over a corresponding period of time. Heart rate correlated significantly with respiratory rate (r = 0.62***, p < 0.001) and gain in weight (r =−0.31*, p = 0.015), but more conventional measures of severity, such as the ratio of pulmonary to systemic flows, failed to show comparable correlations with clinical symptoms. Respiratory rate was related to levels of norepinephrine (r = 0.47***, p < 0.001) and plasma renin activity (r = 0.65***, p < 0.001). The important impact of autonomic imbalance on respiratory rate was underlined by an analysis of variability of heart rate in 26 infants that showed significantly reduced values for the domains of time and frequency. We were not able to find a conclusive multiple regression model with which to explain the symptom "failure to thrive". Conclusions: A increased heart rate, reduced variability in heart rate, and elevated levels of norepinephrine and renin are significant predictors of clinical symptoms such as tachypnea in infants with congenital cardiac malformations. The neurohormonal hypothesis, in which heart failure is interpreted not only as a hemodynamic derangement but also as a neurohormonal disorder, may be valid for infants with congenital cardiac malformations.