The purpose of this trial is to assess whether MYDICAR can reduce the frequency and/or delay heart failure related hospitalizations in persons with advanced heart failure when added to their maximal and optimized therapy.

Inclusion Criteria:

Unless otherwise specified, screening must be performed within 30 days prior to administration of investigational medicinal product on Day 0 except as noted under Inclusion Criteria #1 and 4. Subjects must meet the following criteria to be eligible for the study:

1. Negative neutralizing AAV1 antibodies (NAb) (titer <1:2 or equivocal) within 90 days of screening.

2. 18-80 years of age, inclusive, at the time of signing the informed consent.

3. Chronic systolic HF due to ischemic or non-ischemic cardiomyopathy. Subjects with ischemic cardiomyopathy must have at least one major coronary vessel with Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow. If a subject has not undergone coronary angiography within 2 months, this criterion may be assessed after the subject is randomized and undergoes angiography just prior to the planned infusion of investigational medicinal product.

   1. Hypertrophic cardiomyopathy is excluded.
   2. Toxic and alcoholic cardiomyopathies are allowed as long as toxin or alcohol exposure has been eliminated and a sufficient amount of limit has elapsed to rule-out spontaneous recovery.

4. Left ventricular ejection fraction (LVEF) ≤35% anytime during the 60-day window prior to administration of investigational medicinal product.

5. Diagnosis of New York Heart Association (NYHA) class II, III or IV HF for a minimum of 90 days prior to screening.

6. Individualized, maximal, optimized HF therapy consistent with American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC) practice guidelines for the treatment of chronic heart failure (ACC/AHA/ESC HF guidelines) and as updated from time to time:

   1. Medical therapy as appropriate to the individual subject including oral diuretic, angiotensin-converting enzyme (ACE) inhibitor (or angiotensin-receptor blocker (ARB) if ACE intolerant) and, as tolerated, beta blocker at approved dosages as labeled in the respective package insert. The choice of beta blocker is limited to those approved for heart failure in all participating countries (bisoprolol, carvedilol or sustained release metoprolol succinate). Unless contraindicated or not tolerated, the addition of an aldosterone antagonist should be considered in the absence of hyperkalemia and significant renal dysfunction and according to evolving standards; the final decision is at the discretion of the investigator. Dosing of the above medications must be stable for a minimum of 30 days prior to screening, although up- or down-titration of diuretics, as medically indicated, is permitted. Enrollment of any subject with any deviation from this combination must be preapproved by the medical monitor.
   2. Resynchronization therapy, if clinically indicated according to ACC/AHA/ESC HF guidelines, must have been implanted at least 6 months prior to screening.
   3. Implantable cardioverter defibrillator (ICD), if clinically indicated according to ACC/AHA/ESC HF guidelines, must have been implanted a minimum of 30 days prior to screening.
   4. Cardiac rehabilitation should be consistent with the Agency for Health Care Policy and Research Clinical Practice Guideline, Number 17, Cardiac Rehabilitation. This does not imply that the potential candidate must be enrolled in a cardiac rehabilitation program at screening or in the future.

7. All women of childbearing potential must have a negative urine pregnancy test prior to administration of investigational medicinal product and agree to use adequate contraception (defined as oral or injectable contraceptives, intrauterine devices, surgical sterilization or a combination of a condom and spermicide) or limit sexual activity to vasectomized partner for 3 months after administration of investigational medicinal product. Men capable of fathering a child must agree to use barrier contraception (combination of a condom and spermicide) or limit activity to post-menopausal, surgically sterilized, or a contraception-practicing partner, for 3 months after administration of investigational medicinal product.

8. Ability to understand and comply with study requirements as evidenced by providing signed written informed consent form and Release of Medical Information Form.

9. Presence of at least one of the following risk factors:

   1. Hospitalization for heart failure within 6 months of screening, or in lieu of hospitalization, at least 2 outpatient interventions for the intended treatment of signs and symptoms of worsening heart failure (e.g., intravenous diuretics, peripheral ultrafiltration)
   2. N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1200 pg/mL (BNP >225 pg/mL) within 30 days of screening; if subject is in atrial fibrillation, NT-proBNP >1600 pg/mL (BNP >275 pg/mL) within 30 days of screening

10. In Germany only: Medically indicated for diagnostic angiography at the clinician's discretion.

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from the study:

1. Any intravenous (IV) therapy with positive inotropes, vasodilators or diuretics within 30 days prior to screening.
2. Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete LV aneurysm.
3. Cardiac surgery, percutaneous coronary intervention (PCI) or valvuloplasty within 30 days prior to screening.
4. Myocardial infarction (MI) (e.g., ST elevation MI [STEMI] or large non-STEMI) within 90 days prior to screening. Large non-STEMI shall be defined >3x upper limit of normal (ULN) for creatinine kinase (CK)-MB or >5x ULN for troponin.
5. Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted left ventricular assist device (LVAD) or cardiac shunt.
6. Likely need for an immediate heart transplant or LVAD implant due to hemodynamic instability.
7. Prior coronary artery bypass grafting (CABG) is not considered ideal for inclusion in the study; however, a potential candidate can be reviewed on a case-by-case basis. Ideally, the orifice of the graft should be easy to engage with a catheter and the graft should perfuse a significant amount of potentially viable myocardium.
8. Known hypersensitivity to contrast agents used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography.
9. Significant, in the opinion of the investigator, left main or ostial right coronary luminal stenosis.
10. Liver function tests (alanine amino transferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase) >3x ULN within 30 days prior to investigational medicinal product administration or known intrinsic liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection).
11. Current or likely need for hemodialysis within 12 months following enrollment or current glomerular filtration rate (GFR) ≤20 mL/minute/1.73 m^2 estimated by Modification of Diet in Renal Disease (MDRD) calculation.
12. Bleeding diathesis or thrombocytopenia defined as platelet count <50,000 platelets/μL.
13. Anemia defined as hemoglobin <9 g/dL, provided that there is no evidence of bleeding.
14. Known AIDS or HIV seropositive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm^3.
15. Diagnosis of, or treatment for, any cancer other than basal cell carcinoma within the last 5 years. (Past medical history of cancer is not exclusionary as long as subject has been disease-free for at least 5 years since the time of diagnosis and treatment).
16. Previous participation in a study of gene transfer; however, if the study was unblinded or documentation otherwise exists that the subject was randomized to the placebo control group and did not receive active gene transfer agent, the subject may be considered for this study.
17. Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the investigational drug administration prior to screening. Exception may be made if the individual is enrolled in a non-therapeutic observational study (registry) or the observational portion of a therapeutic study where the sponsoring authority authorizes enrollment.
18. Pregnant or breast-feeding.
19. Recent history of psychiatric disease, including drug or alcohol abuse, that is likely to impair, in the opinion of the investigator, the subject's ability to comply with protocol-mandated procedures.
20. Other concurrent medical condition(s) that, while not explicitly excluded by the protocol, could jeopardize the safety of the subject or objectives of the study.