ALlogeneic Cardiosphere-derived Stem Cells (CDCs) for Pulmonary Hypertension therApy

Patients with IPAH, HPAH, PAH-CTD and PAH-HIV meeting all inclusion and no exclusion criteria will be enrolled. An open label phase 1a study (evaluating dosage and safety) will be conducted. This will followed by a randomized double blind placebo controlled Phase 1b study after Data Safety and Monitoring Board (DSMB) review of the one-month safety data for all the Phase 1a subjects. All patients must have documented PAH diagnosed within the last 5 years and all need to be on stable background PAH specific agents for at least 4 months. The 4 different etiologies of Pulmonary Arterial Hypertension (PAH) included in this (IND) (IPAH, HPAH, PAH-CTD, PAH-HIV) will be diagnosed based on the following: i) clinical features and tests to support a diagnosis of PAH: the diagnosis of PAH requires right heart catheterization (RHC) to confirm a hemodynamic profile compatible with PAH. This includes a mean pulmonary artery pressure (PAP) ≥ than 25 mmHg at rest, with a pulmonary capillary wedge pressure \< 15 mmHg. (If slightly elevated, will confirm with LVEDP measure as is our usual standard of care) and pulmonary vascular resistance (PVR) of \> 3 Wood units. In addition, there should be no features to suggest other associations for PAH (also included in Group 1) or evidence to suggest PAH owing to left heart disease (Group 2), PH due to lung diseases (Group 3), Chronic thromboembolic pulmonary hypertension (Group 4) or miscellaneous disorders of unclear mechanism ii) clinical features and tests to support a specific designation of each subset of PAH: * Idiopathic PAH (IPAH): This is a diagnosis of exclusion in which a firm diagnosis of PAH is made and there are no other etiologies or associations determined that fall into Group 1 * Heritable PAH (HPAH): This diagnosis is based on a family history of PAH with or without a documented genetic mutation associated with PAH (such as BMPR2 mutations that are present in up to 75% of HPAH patients). No other PAH association is present. * PAH - Connective Tissue Disease (PAH-CTD): These patients have a confirmed diagnosis of PAH as well as firm evidence to support a diagnosis of a connective tissue disease. In the REVEAL registry, scleroderma-associated PAH accounted for 60% of PAH-CTD . All PAH-CTD cases will be referred by or evaluated by a rheumatologist to ensure a firm diagnosis. While all CTDs can be complicated by PAH, the most common associations are described below. 1. Scleroderma (SSc): We use the ACR/EULAR criteria for the diagnosis and classification of systemic sclerosis. Patients with SSc-APAH may exhibit features of limited scleroderma, such as, calcinosis, Reynaud's, esophageal dysmotility, sclerodactyly (with skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints) and telangiectasia. In those with limited scleroderma anticentromere antibodies are commonly positive. In patients with diffuse cutaneous scleroderma, SSc-PAH can also be seen. They exhibit diffuse skin thickening and tightening. Anti-topoisomerase antibodies (anti Scl70) may be positive but interestingly, their absence is more likely to be associated with PAH. Other autoantibodies that are associated with an increased risk of SSc-PAH include anti-U1-ribonucleoprotein antibodies (RNP), nucleolar pattern of anti-nuclear antibody (nucleolar-ANA), and rarely antiphospholipid antibodies. 2. Systemic Lupus Erythematosus (SLE): We use the Systemic Lupus International Collaborating Clinics (SLICC) classification, which requires at least 4/17 criteria including at least 1 clinical criterion and 1 immunologic criterion or biopsy proven lupus nephritis. On history and physical exam, the following are highly suggestive: Photosensitive skin lesions (malar rash or discoid lesions), painless ulcers (oral or nasal), features of a serositis, alopecia, Raynaud's, arthralgia/arthritis (often migratory) etc. Immunologic antibody studies included in SLICC are: Positive ANA, anti-dsDNA, anti-Sm, antiphospholipid, low complement, positive direct Coombs test. 3. Mixed Connective Tissue Disease (MCTD): This is characterized by overlapping features of SLE, SSc and polymyositis (PM), as well as high titers of anti-U1 ribonucleoprotein (RNP). The old term for this is anti-extractable nuclear protein (anti-ENA). 4. Rheumatoid Arthritis (RA): RA is a symmetrical distal inflammatory poly arthritis condition. The criteria developed and validated by the American College of Rheumatology (ACR) has been used in numerous drug studies which requires at least four of these seven criteria for diagnosis (morning stiffness, arthritis of three or more joint areas, arthritis of the hands, symmetric arthritis, rheumatoid nodules and classic radiographic erosive changes). Immunologic studies include positive rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibody. * PAH- Human Immunodeficiency Virus (HIV): Patients will have a firm diagnosis with positive HIV testing (i.e. positive 4th generation immunoassay and positive confirmatory testing such as Western Blot or HIV-1/HIV-2 antibody differentiation immunoassay) and managed by an infectious disease/HIV specialist. These patients have hemodynamic criteria for PAH present, but the only association on workup is the presence of HIV.