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Distinct genomic replacements from Lewis correct diastolic dysfunction, attenuate hypertension, and reduce left
Alan Y Deng1, Stanley Nattel, Yanfen Shi
1Research Centre, Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada. alan.deng@umontreal.ca
Insights
Researchers identified novel genetic factors influencing diastolic heart failure in rats. Two congenic strains normalized diastolic dysfunction, offering new insights into hypertension and heart failure treatments.
Area of Science:
- Cardiovascular Genetics
- Physiology
- Animal Models
Background:
- Hypertension and diastolic heart failure are leading causes of cardiovascular morbidity and mortality.
- Understanding the genetic basis of polygenic hypertension and diastolic heart failure is crucial.
- Dahl salt-sensitive rats are a model for diastolic heart failure, but its genetic determinants are unknown.
Purpose of the Study:
- To identify quantitative trait loci (QTLs) for blood pressure and diastolic dysfunction.
- To develop and characterize congenic rat strains for studying genetic contributions to diastolic heart failure.
- To investigate the relationship between blood pressure regulation and cardiac function.
Main Methods:
- Echocardiography was used to assess cardiac phenotype and diastolic function in Dahl salt-sensitive and Lewis rats.
- Congenic rat strains, created by chromosome substitution, were analyzed for blood pressure and diastolic function.
- Cardiac function and left ventricular mass were evaluated in six congenic strains.
Main Results:
- Dahl salt-sensitive rats exhibited diastolic dysfunction.
- Two of six congenic strains (positive congenic strains) normalized diastolic dysfunction and reduced left ventricular mass.
- Four congenic strains lowered blood pressure but did not improve diastolic function.
Conclusions:
- Novel genetic loci influencing diastolic function and left ventricular mass were identified in the positive congenic strains.
- These findings suggest previously unrecognized genes contribute to diastolic dysfunction.
- This research may lead to new strategies for treating hypertensive diastolic heart failure.
Background:
Hypertension and diastolic heart failure are two common cardiovascular diseases that inflict heavy morbidity and mortality, yet relatively little is understood about their pathophysiology. The identification of quantitative trait loci for blood pressure is important in unveiling the causes of polygenic hypertension. Although Dahl salt-sensitive strain is also an excellent model for the study of diastolic heart failure, virtually nothing is known about the quantitative trait loci determining diastolic heart failure. Diastolic dysfunction often represents the onset of diastolic heart failure.
Methods:
We first characterized the cardiac phenotype of Dahl salt-sensitive strain and normotensive Lewis control rats by echocardiography to ascertain diastolic function. We then analyzed corresponding features of four newly developed and two existing congenic strains, each of which carries a specific chromosome substitution of Dahl salt-sensitive strain by its Lewis homologue and each lowering blood pressure.
Results:
Dahl salt-sensitive strain displayed diastolic dysfunction that was rectified in two of six congenic strains, designated as positive congenic strains, which represent the first rodent models exhibiting functional normalization of diastolic dysfunction caused by naturally occurring genetic variants. The two positive congenic strains also showed a reduction in left ventricular mass. In contrast, four of six congenic strains did not change diastolic function despite their blood pressure-lowering effects.
Conclusion:
Genes present in the replaced chromosome segments of the two positive congenic strains are not commonly known to affect blood pressure, diastolic function or left ventricular mass. Consequently, novel prognostic, diagnostic and therapeutic strategies for hypertensive diastolic heart failure likely emerge from this work.
