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Endothelin in human congestive heart failure
C M Wei1, A Lerman, R J Rodeheffer
1Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905.
Insights
In severe congestive heart failure (CHF), elevated plasma endothelin (ET) is mainly the precursor big-ET, not the active ET-1. Cardiac ET remains ET-1 and unchanged, with plasma ET correlating to CHF severity.
Area of Science:
- Cardiovascular Research
- Biochemistry
- Molecular Biology
Background:
- Plasma endothelin (ET) elevation in congestive heart failure (CHF) is reported, but its molecular form (ET-1 vs. big-ET) and myocardial involvement are unclear.
- It is unknown if ET levels increase in early CHF stages (asymptomatic left ventricular dysfunction) and correlate with ventricular dysfunction severity.
Purpose of the Study:
- To investigate plasma and cardiac tissue endothelin (ET) concentrations and molecular forms in healthy individuals and CHF patients across New York Heart Association (NYHA) classes I-IV.
- To determine the relationship between circulating ET levels and the severity of cardiac dysfunction and functional class in CHF.
Main Methods:
- Utilized cardiac radionuclide angiogram, myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS).
- Analyzed plasma and cardiac tissue samples from healthy subjects and CHF patients (NYHA class I-IV).
Main Results:
- Plasma ET increased significantly in moderate (NYHA III) and severe (NYHA IV) CHF, correlating negatively with left ventricular ejection fraction and positively with functional class.
- In severe CHF, plasma ET comprised both mature ET-1 and its precursor big-ET, with big-ET being predominant; cardiac ET remained ET-1 and was present in both healthy and failing hearts.
- Circulating ET elevation was specific to severe CHF and correlated with hemodynamic alterations and functional class.
Conclusions:
- Elevated plasma ET in severe CHF is primarily due to the precursor big-ET, not mature ET-1.
- Cardiac endothelin (ET) is present in both healthy and failing hearts as ET-1 and its activity is unchanged in CHF.
- Increased plasma ET is characteristic of severe CHF and correlates with disease severity and hemodynamic impairment.
Background:
Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction.
Methods And Results:
The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts.
Conclusions:
The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.