PAHTCH Pulmonary Arterial Hypertension Treatment With Carvedilol for Heart Failure (Carvedilol)

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature leading to elevated pulmonary pressure and right ventricular (RV) dysfunction with heart failure. Measures of RV function are better predictors of mortality and long term outcomes than pulmonary vascular resistance. The interaction between RV function and the pulmonary circulation is not fully understood, but increased after load appears insufficient to explain right heart failure. Yet, all approved PAH therapies target vasodilation of the pulmonary vasculature to lower pressures

Pulmonary arterial hypertension (PAH) is a serious condition characterized by endothelial dysfunction leading to pulmonary vascular constriction, smooth muscle and endothelial proliferation, and progressive right-sided heart failure. The severity of pulmonary hypertension is mostly determined by the response of the right ventricle (RV) to the increased afterload or pulmonary pressures, and RV failure is the leading cause of death in PAH. Most accepted therapies for PAH have been aimed at vasodilation of the pulmonary vasculature, and there has been little thought that PAH patients would benefit from traditional left heart failure treatments. A cornerstone therapy in left heart failure is £\]-adrenergic receptor blockade because of its ability to reverse cardiac remodeling and improve clinical outcomes, despite decades of concern regarding its propensity to exacerbate heart failure. It has been reported to reduce mortality by about 30% in patients, and while the precise mechanisms that contribute to its beneficial effects remain to be elucidated, there is evidence that patients with underlying contractile reserve (i.e., via recruitment of viable myocardium with £\]-adrenergic receptor stimulation) may experience greater recovery of their cardiac function. In a study using rats with pulmonary hypertension treated with £\] blocker, RV function improved, and maladaptive myocardial remodeling was prevented.

Eligibility Criteria:
Inclusion Criteria:

* Men and women age 18 or older not greater than age 65 years
* Diagnosis of pulmonary arterial hypertension class 1, 3, 4, 5 (Dana Point 2008)
* NYHA (New York Health Association)/WHO (World Health Organization) Class I-III
* PAH medications must have been initiated according to the latest consensus statement recommendations and remained stable for the last 30 days
* Women of child-bearing age must use a double-barrier local contraception till completion of the study
* Subjects must demonstrate understanding of the study, sign the informed consent, and have a reliable method of communication for contact and ability to comply with the study requirements

Exclusion Criteria:

* Participation in any other treatment studies during enrollment
* Significant illness in the past 30 days requiring hospitalization
* Hepatic insufficiency (transaminase levels \> 4 fold the upper limit of normal or bilirubin \> 2 fold the upper limit of normal),
* History of HIV, Hepatitis B or C
* Serum creatinine \> 2.8 mg/dl
* Pregnancy, breast-feeding, or lack of safe contraception
* Acute decompensated heart failure within past 30 days
* Known allergy or intolerance to carvedilol or other β blockers
* Significant, persistent bradycardia (resting heart rate \< 50 bpm) or hypotension (systolic blood pressure \< 100 mmHg or mean blood pressure \< 70 mmHg) at the time of enrollment
* Second or third-degree AV (Atrial Ventricular) block without pacemaker
* Use of CYP2D6 isoenzyme inhibitors (such as quinidine, fluoxetine, paroxetine, propafenone) which increase drug levels and result in greater vasodilating effects and hypotension
* Use of hypotensive drugs that deplete catecholamines (such as reserpine and monoamine oxidase inhibitors) which may lead to greater signs of hypotension or bradycardia
* Other medical and psychosocial conditions as determined by principal investigator deemed unsuitable for enrollment