Related Experiment Videos
Lymphocyte G proteins reflect response to treatment in congestive heart failure
E M Horn1, M L Kukin, G W Neuberg
1Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, N.Y.
Insights
Patients with congestive heart failure showed altered G protein activity after vasodilator treatment. Nonresponders exhibited increased norepinephrine and Gi, indicating a poor response to heart failure therapy.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Congestive heart failure (CHF) is linked to reduced responsiveness to adrenergic stimulation.
- Altered G protein activity, specifically decreased Gs alpha or increased Gi alpha, can impair adenylyl cyclase function in CHF.
Purpose of the Study:
- To investigate G protein responses to direct-acting vasodilator treatment in severe CHF patients.
- To correlate changes in lymphocyte beta-adrenergic receptor components with hemodynamic improvements.
Main Methods:
- Studied 23 patients with severe CHF (NYHA classes III-IV), categorized into responders (n=10) and nonresponders (n=13).
- Assessed hemodynamic variables, plasma norepinephrine levels, and lymphocyte G protein (Gs and Gi) components before and after vasodilator therapy.
Main Results:
- All patients showed improved cardiac index and reduced blood pressure and systemic vascular resistance.
- Responders experienced significant decreases in left ventricular filling pressure and right atrial pressure.
- Nonresponders showed a significant increase in plasma norepinephrine and lymphocyte Gi, with no significant change in filling pressures.
Conclusions:
- Poor response to vasodilators in CHF is characterized by elevated plasma norepinephrine and lymphocyte Gi.
- These molecular changes in nonresponders may contribute to their limited hemodynamic improvement.
- Direct-acting vasodilators impact G protein signaling differently in CHF responders versus nonresponders.
Abstract:
Congestive heart failure is associated with chronotropic and inotropic hyporesponsiveness to adrenergic stimulation. A decrease in Gs alpha or an increase in Gi alpha is associated with a decrease in adenylyl cyclase activity. The current study assessed G proteins in response to treatment with direct-acting vasodilators and correlated changes in lymphocyte beta-adrenergic receptor components with changes in hemodynamic variables. Twenty-three patients with severe chronic congestive heart failure (New York Heart Association functional classes III and IV) were studied. Patients were grouped as responders (n = 10) or nonresponders (n = 13) on the basis of clinical assessment of functional status from questionnaires. Therapy was associated with an increase in cardiac index, a decrease in mean arterial pressure, and a decrease in systemic vascular resistance in all patients. Left ventricular filling pressure significantly decreased in responders (26 +/- 2 mm to 13 +/- 3 mm, p < 0.05) but did not change significantly in nonresponders. Similarly, mean right atrial pressure significantly decreased in responders (11 +/- 2 mm Hg to 4 +/- 1 mm Hg, p < 0.05) but did not change in nonresponders. Plasma norepinephrine increased significantly only in nonresponders (679 +/- 100 pg/ml to 1233 +/- 201 pg/ml, p < 0.05). Whereas lymphocyte beta-adrenergic receptor density and Gs did not significantly change, Gi increased after treatment only in the nonresponder group (23 +/- 5 to 51 +/- 11 fmol/mg, p < 0.05). A poor response to direct-acting vasodilators can be distinguished by reactive increases in plasma norepinephrine and lymphocyte Gi in the absence of a decrease in either left- or right-sided filling pressures.