Body Volume Regulation in Pulmonary Arterial Hypertenison With Right Ventricular Failure

Much has been learned about the pathophysiological state that underlies the development of
increased total body volume and edema in left ventricular failure. Very little, however, is
known about the mechanism underlying systemic hypervolemia in patients with isolated right
ventricular dysfunction. Patients with pulmonary arterial hypertension (PAH) represent a
model of isolated right ventricular dysfunction in which these mechanisms may be elucidated.
Aldosterone has now been shown to have many properties that are likely to be detrimental in
congestive heart failure (CHF) and that are not shared by angiotensin II. Aldosterone
blockade has been associated with improved mortality in patients with left ventricular
failure, already receiving an angiotensin converting enzyme inhibitor. But its role in
isolated right ventricular failure has not been elucidated. The plasma arginine vasopressin
levels are disproportionately elevated for the degree of serum osmolarity in patients with
heart failure and result in water retention and hyponatremia. Conivaptan, a vasopressin
receptor antagonist, appears to reduce body weight and improve signs of left heart failure,
though there is no study to evaluate its role in right ventricular failure with edema.

This study will examine the role of spironolactone and conivaptan in patients with right
ventricular failure and pathophysiology of sodium and water retention in these patients.

Inclusion Criteria:

1. Patients with WHO group 1 pulmonary arterial hypertension [51], excluding patients with
portal hypertension, meeting the following hemodynamic parameters:

- Mean pulmonary artery pressure (mPAP) >35 mmHg at rest, and

- Pulmonary capillary wedge pressure (PCWP) <15 mmHg, and

- Pulmonary vascular resistance (PVR) >1.5 wood units, and 2. Age 18 to 75 years 3.
Right ventricular failure defined by right atrial pressure >7 mmHg along with either
dilated right ventricle, or absence of inferior vena cava collapse or BNP >100 pg/ml
4. Patients of childbearing age must be practicing effective birth control. 5. Normal
left ventricular function as assessed by echocardiogram, multiple gated acquisition
(MUGA) cardiac scan, or invasive left ventriculography.

Exclusion Criteria:

1. Group 2-5 pulmonary hypertension as defined by WHO.

- Pulmonary hypertension with left heart failure (as assessed by echocardiogram,
multiple gated acquisition (MUGA) cardiac scan, or invasive left ventriculography).

- Pulmonary hypertension associated with lung disease and/or hypoxemia (e.g. chronic
obstructive pulmonary disease, interstitial lung disease, sleep disordered breathing,
chronic exposure to high altitude, alveolar hypoventilation syndrome.

- Pulmonary hypertension due to chronic thrombotic and/or embolic diseases

- Miscellaneous such as sarcoidosis, compression of pulmonary vessels by adenopathy,
tumor 2. Systemic hypertension, defined as a systolic pressure >140 mmHg or a
diastolic blood pressure >90mmHg 3. Patients taking angiotensin converting enzyme
(ACE) inhibitor or angiotensin receptor blockers (ARBs) 4. Pregnancy 5. Chronic
kidney disease (serum creatinine > 2.5mg/dl, proteinuria >500 mg/day, hematuria) 6.
Cirrhosis or portal hypertension 7. Inability to provide informed consent. 8. Allergy
to conivaptan or spironolactone. 9. Active malignancy 10. Patients receiving
spironolactone 11. Enrollment in other interventional studies. 12. Patients on HAART