Basic Science and Experimental Studies
Left ventricular response to sustained volume overload from chronic aortic valve regurgitation in rats*,**,***

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Abstract

Objectives: Aortic regurgitation (AR) induces left ventricular (LV) eccentric hypertrophy in response to chronic volume overload. Patients suffering from this disease often remain asymptomatic for decades before progressive LV dysfunction develops silently. Because of this slow evolution, large clinical trials with long-term follow-up on subjects with chronic AR are hard to perform. To overcome this problem, animal models have been developed in the past but results were very heterogeneous. Methods: Helped by echocardiography, we refined a known technique to induce homogenous degrees of severe AR in Wistar-Kyoto rats. The effects on LV function without treatment and with nifedipine (25 mg/kg daily) (a drug currently recommended in humans with chronic AR) were evaluated by echocardiography. Results: Over 6 months, nontreated animals developed progressive LV dilatation and eccentric hypertrophy, characteristic of chronic LV volume overload. The animals also developed progressive LV systolic dysfunction, mimicking closely the evolution of the disease in humans. Abnormal filling parameters were also detected in the majority of animals. Systolic and diastolic abnormalities were prevented but only partially in the group treated with nifedipine. Conclusion: This model can be used to study chronic AR and LV dysfunction associated with the disease. Nifedipine seems to protect the LV against chronic volume overload but only partially. Treatment strategies currently used in humans deserve further investigation.

Section snippets

Animals

Fifty-three male Wistar rats (body weight 325-375 g) were used in this protocol.

Acute AR

The animals were randomly divided in 3 study groups of 8 to 10 subjects as follows: (#1) acute AR studied 24 hours after surgical procedure (described later in this article), (#2) acute AR studied 48 hours after surgical procedure, and (#3) AR studied 2 weeks after surgical procedure (transition phase from acute to chronic).

Chronic AR

The animals were divided in 3 study groups of 8 to 10 subjects as follows: (#1) normal

Survival rate

All animals in the control group and in the nontreated AR group survived until the end of the protocol. One animal died of acute heart failure in the nifedipine-treated group. None of the surviving animals required medical treatment for heart failure.

Left ventricular dimensions

Figure 1 depicts the evolution of LV dimensions, mass, and ejection fraction in the acute period up to 2 weeks.

. Evolution of echocardiographic parameters after acute aortic regurgitation. The left column depicts the results obtained in the animals

Discussion

We describe in this article the natural and progressive evolution of volume overload cardiomyopathy in a rat model of chronic AR. With the help of echocardiographic guidance,25 we were able to induce consistently severe AR and significant systolic dysfunction (defined as an ejection fraction below 50%) with eccentric hypertrophy after 26 weeks in our animals.

We used the same echocardiographic criteria that are routinely used clinically in humans to assess the severity of aortic regurgitation in

Conclusion

Over the 6 month follow-up, we encountered the whole spectrum of volume overload cardiomyopathy in our animals ranging from a normal sized, nonhypertrophied hypercontractile LV in the acute phase (also seen in humans with acute severe AR) to severely dilated, eccentrically hypertrophied, and hypocontractile left ventricles in the end of the chronic phase (also seen in humans with decompensated AR volume overload cardiomyopathy). This model therefore allows the study of the disease in all its

Acknowledgements

The authors want to acknowledge the precious technical assistance of André Blouin during the surgical procedures.

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    *

    This work was funded by the Heart and Stroke Foundation of Canada and the Quebec Heart Institute Foundation. Dr. Couet is a scholar of the Canadian Institutes of Health Research. Dr. Arsenault is a scholar of the Fonds de la Recherche en Santé du Québec.

    **

    Reprint requests: Jacques Couet, PhD, Groupe de Recherche sur les Valvulopathies, Centre de Recherche Hôpital Laval, 2725 chemin Sainte-Foy, Sainte-Foy, Québec, Canada, G1V 4G5.

    ***

    1071-9164/03/0902-0009$30.00/0

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