What can promote angiogenesis in the heart?

Cardiac Angiogenesis Promotion

Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) are the primary angiogenic factors that promote new blood vessel formation in the heart, though their clinical efficacy remains limited despite promising animal data. 1

Primary Angiogenic Growth Factors

VEGF (Vascular Endothelial Growth Factor)

• VEGF is the fundamental regulator of vascular growth and the key target for therapeutic angiogenesis in cardiac tissue. 2
• Promotes endothelial cell proliferation, migration, and tube formation to induce new blood vessel development 1
• Can be delivered as recombinant protein or via gene therapy using adenovirus-mediated transfer of VEGF cDNA 1
• Requires sustained expression of at least 4 weeks in vivo to achieve stable vessels that persist after cessation of the angiogenic stimulus 2
• Critical limitation: VEGF has a very narrow therapeutic window—low doses are safe but inefficient, while higher doses rapidly become unsafe 2

FGF-2 (Fibroblast Growth Factor-2)

• Demonstrated therapeutic usefulness in large-animal models of chronic myocardial ischemia for improving myocardial perfusion 1
• Works synergistically with VEGF to promote angiogenesis 3, 4
• Can be administered via intra-arterial or intramuscular routes 1

Additional Angiogenic Mediators

Angiopoietin-1 (Ang-1)

• Responsible for recruitment and stable attachment of pericytes, leading to maturation of newly formed blood vessels 1
• Works in coordination with VEGF to stabilize new vessel formation 1

Insulin-Like Growth Factor-1 (IGF-1)

• Major regulator of adaptive/physiological cardiac hypertrophy and promotes cardiomyocyte survival 1
• Important source produced by cardiac fibroblasts during remodeling 1

Hypoxia-Inducible Factor-1

• Promotes collateral blood vessel formation and increases limb blood flow in experimental models 1
• Can be delivered via gene transfer with naked plasmid DNA or adenoviral vectors 1

Critical Clinical Translation Challenges

Why Animal Success Hasn't Translated to Patients

The failure of VEGF and FGF-2 in clinical trials is attributed to deficiency in stimulated nitric oxide release in diseased human myocardium. 1

• Disease states (coronary artery disease, hypercholesterolemia) significantly alter nitric oxide production and other factors 1
• Endothelial dysfunction plays a crucial inhibitory role in response to exogenous angiogenic agents 1
• Increased vascular oxidative stress in patients blocks the angiogenic response seen in healthy animal models 1

Potential Solutions to Overcome Clinical Failure

Adjuvant therapy with L-arginine or inhibitors of oxidative stress may increase effectiveness of growth factor or gene therapy. 1

• L-arginine serves as the precursor for nitric oxide synthesis and may restore the angiogenic response 1
• Antioxidant therapy to reduce vascular oxidative stress could enhance angiogenic factor efficacy 1

Delivery Methods

Protein-Based Delivery

• Direct administration of recombinant VEGF or FGF-2 proteins 1
• Intra-arterial administration via femoral artery 1
• Intramuscular injection into ischemic myocardium 1

Gene Therapy Approaches

• Adenovirus-mediated transfer of VEGF cDNA for sustained expression 1
• Naked plasmid DNA delivery 5
• Requires minimally invasive techniques to reduce administration risks 1

Cell-Based Therapy

• Bone marrow stem cells, peripheral stem cells, and skeletal muscle myoblasts can promote angiogenesis 1
• Pretreatment of infarcted myocardium with angiogenic factors enhances survival of transplanted cells 1
• Cellular cardiomyoplasty has demonstrated feasibility and safety in phase I European trials 1

Biomaterial-Based Delivery

• Polymeric biomaterials provide three-dimensional drug-releasing depot for temporally and spatially controlled release 6
• Biomimetic signals can be incorporated for environmentally-responsive or cell-triggered release 6

Clinical Context and Indications

Therapeutic angiogenesis is being investigated for the 10-12% of patients with severe coronary artery disease who are not candidates for standard revascularization techniques. 1

• Can be used as adjunct to conventional surgical procedures 1
• Targets patients with "no-option" coronary disease not amenable to angioplasty or bypass surgery 3, 4
• May help prevent progression of coronary artery disease and treat ventricular dysfunction 1

Important Caveats

• Despite promising preclinical data, clinical trials have consistently failed to demonstrate that therapeutic angiogenesis is as effective in patients as in animal models 1
• New imaging technologies (CT, MRI, PET) are required to assess efficacy of angiogenic therapy 1
• Large-scale randomized placebo-controlled studies are still needed to demonstrate true clinical benefit 4
• Given current evidence, it remains premature to make definitive recommendations regarding efficacy and safety of angiogenic growth factors for cardiac treatment 1
• Potential side effects include limb edema, proteinuria, and theoretical concerns about promoting tumor angiogenesis 1