The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment

There is now strong evidence from clinical trials that carvedilol therapy in heart failure is superior to therapy with metoprolol. Not only does carvedilol have superior effects on lipid profiles, insulin sensitivity, renal blood flow, and reversal of pathologic remodeling but also its use is associated with fewer deaths compared to metoprolol. These facts make it important to carefully define how metoprolol and carvedilol are pharmacologically different. One potential difference is α1-AR antagonism. If we demonstrate that these α1-AR effects are preserved with chronic therapy, then α1-AR blockade may have an important role in carvedilol favorably altering the natural history of heart failure. On the other hand, if we demonstrate that tolerance to the α1-AR blockade effect of carvedilol decreases with time, then it would be unlikely that this pharmacologic property contributes to the efficacy of carvedilol. In such a case other pharmacologic properties, such as antioxidant activity, would appear to be important. These results will help guide future studies into CHF and AR blockade.

Inclusion Criteria:

1. Age of 18 to 85 years
2. Symptomatic heart failure, NYHA class I to III
3. Left ventricular ejection fraction < 0.40
4. Give written informed consent

Exclusion Criteria:

1. active myocarditis
2. congenital heart disease
3. uncorrected, hemodynamically significant stenotic valvular disease
4. hypertrophic cardiomyopathy
5. Asthma or other obstructive airway diseases requiring bronchodilators
6. Heart rate < 60 beats/min, supine systolic blood pressure < 85 mm Hg, supine diastolic blood pressure > 90 mm Hg
7. Uncontrolled Hypertension (Systolic BP >140 mmHg, Diastolic BP > 90 mmHg).
8. Sick sinus syndrome, Mobitz type 2 second degree AV block or third degree AV block unless controlled with an artificial implantable pacemaker
9. NYHA functional class IV symptoms
10. Treatment with an excluded medication (see Excluded Medications below)
11. Myocardial infarction or coronary artery intervention (CABG or angioplasty) within three months
12. Unstable angina pectoris
13. Presence of any progressive systemic disease that would be expected to impact the patient's outcome over the time course of the study
14. Uncorrected endocrine disorders including primary aldosteronism, pheochromocytoma, hyperthyroidism, hypothyroidism, brittle type 1 diabetes mellitus
15. Evidence of significant renal disease (serum creatinine > 2.5 mg/dl), or hepatic disease (transaminase level > three fold higher than laboratory normal)
16. Symptomatic peripheral vascular disease
17. Inability or unwillingness to cooperate with study or give written informed consent