Left ventricular remodeling is a major cause of heart failure and death after myocardial infarction. Dr. Soeki and colleagues have previously shown that C-type natriuretic peptide (CNP) inhibits DNA and collagen synthesis by fibroblast more potently than atrial and brain natriuretic peptides in vitro.

Because CNP appears to have potent inhibitory effects on cardiac fibrosis and hypertrophy in vitro, investigators hypothesized that CNP might attenuate the cardiac late remodeling that can occur after myocardial infarction in vivo. To assess this hypothesis, Dr. Soeki and colleagues observed the effects of CNP on progression of cardiac remodeling in a rat model of myocardial infarction.

The researchers used coronary artery ligation to induce experimental myocardial infarction in male rats. Then, some of these rats received a CNP infusion at 0.1 μg/kg per minute for 2 weeks, beginning 4 days after the infarction. A second group of rats received vehicle only, which consisted of a 5% glucose solution. A third group of rats underwent a sham surgical procedure with no coronary ligation.

To determine effects on systolic blood pressure and pulse rate, investigators took measurements before myocardial infarction and at 1 day, 1 week, and 2 weeks after infarction. As a result, the systolic blood pressure and pulse rate were not perturbed by CNP infusion at any time points. Investigators also performed echocardiographic studies 4 and 18 days after the coronary ligation or sham operation. They excluded rats from the study that had fractional shortening of more than 20% or an E wave to A wave ratio of less than 3 in the echocardiography performed 4 days after MI.

Final analysis on the 18th day of the study included 34 rats that had an infarction and received CNP, 35 rats that had an infarction but received only vehicle, and 34 rats that underwent sham operation.

Although left ventricular end-diastolic dimension was greater in the rats that underwent coronary ligation than in rats that underwent the sham operation, CNP infusion did significantly attenuate left ventricular enlargement.

They also found CNP treatment significantly improved systolic and diastolic left ventricular dysfunction without affecting arterial pressure. In the group that did not receive CNP, left ventricular end-diastolic pressure was higher than in the sham group, and the peak rate of contraction (dP/dtmax), the peak rate of relaxation (dP/dtmin), and cardiac output was lower.

Dr. Soeki also reported that CNP attenuated increase of morphometrical collagen volume fraction in the non-infarct region.

The CNP infusion also significantly improved capillary density, which was reduced by myocardial infarction, in the non-infarct region.

In addition, CNP prevented an increase in the heart weight to body weight ratio and hypertrophy of the cardiomyocytes in the non-infarct region.

Finally, CNP suppressed increases of collagen 1 and collagen 3 mRNA levels associated with fibrosis in the non-infarct region. The CNP infusion also suppressed increases of atrial natriuretic peptide and β-myosin heavy chain mRNA levels associated with cardiac hypertrophy.

These results suggest that in vivo CNP administration can improve left ventricular dysfunction and attenuate cardiac remodeling. The CNP infusion appeared to have beneficial effects on cardiac performance. However, it had very little effect on blood pressure, heart rate, and infarct size. This suggests some mechanism other than hemodynamic improvement or reduction in size of infarct would explain the beneficial effects of CNP.

One possibility is that CNP directly inhibits myocardial fibrosis. Another possibility is that CNP attenuates myocardial hypertrophy after myocardial infarction. Some research suggests CNP may activate the vascular endothelial cGMP/cGMP-dependent protein kinase pathway; through this, CNP may improve the reduced cardiac capillary density after myocardial infarction, leading to less impairment of left ventricular function.

Regardless of the mechanism, the results of this study suggest the potential usefulness of CNP as a new cardioprotective agent.