Recent treatment modalities for cardiovascular diseases with a focus on stem cells, aptamers, exosomes and nanomedicine

Figures & data

Figure 1. Stem cell therapy in cardiovascular disease. Potential sources of stem cell therapy for cardiovascular disease are bone marrow-derived cells, inducible pluripotent stem cells, resident cardiac stem cells, mesenchymal or adipose tissue-derived stem cells, skeletal myoblasts, and circulating stem cells. Once differentiated into cardiospheres, they can be directly injected into an infarct zone or indirectly delivered to an ischemic zone via intracoronary or transcoronory cell injection.

Table 1. Application of stem cell therapy for the treatment of cardiovascular diseases.

Type of disease	Intervention	Results	References
Myocardial infarct	Multipotent stem cells	Increase in EF, FS	[8]
Myocardial infarct	Skeletal myoblasts	Increase in EF, decrease in EDV	[9]
Ischemic heart disease	BMMNC	+7.0 to +2.8% increase in EF, decreased mortality	[10,12,13]
Ischemic heart disease	BMC	+9.2% increase in EF	[10]
Heart failure	BMC	+6.3% increase in EF; −9.5% decrease in EDV	[11]
Heart failure	Mesenchymal stem cells	+7% increase in EF; improved 6 min walk distance	[14]

EF: ejection fraction; FS: functional shortening (ventricular diameter during systole); EDV: end diastolic volume; BMMNC: bone-marrow mononuclear cells.

Figure 2. Drug-eluting and biodegradable stent in coronary artery. Drug-eluting and biodegradable stents maximize the effectiveness of stent in atherosclerosis while minimizing side effects. These stents allow specific drug delivery into endothelial and smooth muscle cells in the affected area, and decrease chances of inflammatory process and restenosis. Stents are covered by polymer coating, which can be degraded gradually as drug delivery is completed.

Figure 3. Nanoparticle drug delivery to ischemic cardiac myocyte. A nanoparticle specific for ischemic cardiac myocyte is prepared by following: addition of organic spacers, attachment of functional groups (e.g. NH₂) to organic spacers, and binding of Annexin V on the surface of a nanoparticle. Then, this newly assembled nanoparticle is intravenously injected, and delivered to the infarct area. Here, Annexin V on the nanoparticle recognizes phopshatidylserine expressed on the surface of a cardiac myocyte and successfully delivers drug content into the cell.

Table 2. Targeted drug delivery for cardiovascular diseases using nanoparticles.

Disease	Therapy	Material	Particle size (nm)	Payload	Effect	References
Atherothrombotic disease	Polysaccharide/polymer-based nanosystem	PLGA	100	bFGF	Increased arteriole density	[55]
		Gold	124	VEGF conjugated to surface	Increased vascular density	[56]
		PLGA	297	Heparin	Decreased necrosis, increased HGF expression	[74]
	Superparamagnetic iron oxide nanoparticles with cross-linked dextran coating (CLIO)	Dextran-co-gelatin	130	VEGF	Increased, collateral vessel density	[75]
Injured myocardium	Polysaccharide/polymer-based nanosystem	PLGA/PEI	74	IGF-1	Decreased apoptosis, infarct area, increased wall thickness	[76]
		PCADK, coated with GlcNAc	320	p38i	Decreased apoptosis, infarct size	[77]
		polyketal	500	Nox2-NADPH oxidase siRNA	Decreased Nox2 mRNA expression	[78]
	Liposomal	Liposome	150	PGE1, ATP, CoQ10, Adenosine	Decreased infarct size	[79,80]
		P-selectin-conjugated liposome	180	VEGF	Increased capillary, arteriole density, increased Ang-1 expression, decreased infarct size	[81]

PLGA: poly(lactic-co-glycolic acid); bFGF; basic fibroblast growth factor; VEGF: vascular endothelial growth factor; HGF: hepatocyte growth factor; PEI: poly(ethylenimine); IGF-1: insulin-like growth factor; PCADK: poly(cyclohexane- 1,4-dilacetone dimethylene ketal); GlcNAc: N-acetyl-glucosamine; p38i: p38 inhibitor, PGE1: prostanglandin; ATP: adenosine triphosphate; CoQ10: coenzyme; Ang-1: angiotensin.

Pelacho B, Nakamura Y, Zhang J, et al. Multipotent adult progenitor cell transplantation increases vascularity and improves left ventricular function after myocardial infarction. J Tissue Eng Regen Med. 2007;1:51–59.

 PubMed Web of Science ®Google Scholar

Ghostine S, Carrion C, Souza LC, et al. Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation. 2002;106:I131–I136.

 PubMed Web of Science ®Google Scholar

Abdel-Latif A, Bolli R, Tleyjeh IM, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167:989–997.

 PubMed Web of Science ®Google Scholar

Schachinger V, Erbs S, Elsasser A, et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. 2006;27:2775–2783.

 PubMed Web of Science ®Google Scholar

Meluzin J, Janousek S, Mayer J, et al. Three-, 6-, and 12-month results of autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction. Int J Cardiol. 2008;128:185–192.

 PubMed Web of Science ®Google Scholar

Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail. 2010;12:721–729.

 PubMed Web of Science ®Google Scholar

Bartunek J, Behfar A, Dolatabadi D, et al. Cardiopoietic stem cell therapy in heart failure: the C-CURE (cardiopoietic stem cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol. 2013;61:2329–2338.

 PubMed Web of Science ®Google Scholar

Chappell JC, Song J, Burke CW, et al. Targeted delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction for therapeutic arteriogenesis. Small. 2008;4:1769–1777.

 PubMed Web of Science ®Google Scholar

Kim J, Cao L, Shvartsman D, et al. Targeted delivery of nanoparticles to ischemic muscle for imaging and therapeutic angiogenesis. Nano Lett. 2011;11:694–700.

 PubMed Web of Science ®Google Scholar

Lian L, Tang F, Yang J, et al. Therapeutic angiogenesis of PLGA-Heparin Nanoparticle in mouse ischemic limb. J Nanomaterials. 2012;2012:193704.

 Web of Science ®Google Scholar

Xie J, Wang H, Wang Y, et al. Induction of angiogenesis by controlled delivery of vascular endothelial growth factor using nanoparticles. Cardiovasc Ther. 2013;31:e12–e18.

 PubMed Web of Science ®Google Scholar

Chang MY, Yang YJ, Chang CH, et al. Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. J Control Release. 2013;170:287–294.

 PubMed Web of Science ®Google Scholar

Gray WD, Che P, Brown M, et al. N-acetylglucosamine conjugated to nanoparticles enhances myocyte uptake and improves delivery of a small molecule p38 inhibitor for post-infarct healing. J Cardiovasc Transl Res. 2011;4:631–643.

 PubMed Web of Science ®Google Scholar

Somasuntharam I, Boopathy AV, Khan RS, et al. Delivery of Nox2-NADPH oxidase siRNA with polyketal nanoparticles for improving cardiac function following myocardial infarction. Biomaterials. 2013;34:7790–7798.

 PubMed Web of Science ®Google Scholar

Smalling RW, Feld S, Ramanna N, et al. Infarct salvage with liposomal prostaglandin E1 administered by intravenous bolus immediately before reperfusion in a canine infarction-reperfusion model. Circulation. 1995;92:935–943.

 PubMed Web of Science ®Google Scholar

Verma DD, Hartner WC, Levchenko TS, et al. ATP-loaded liposomes effectively protect the myocardium in rabbits with an acute experimental myocardial infarction. Pharm Res. 2005;22:2115–2120.

 PubMed Web of Science ®Google Scholar

Scott RC, Rosano JM, Ivanov Z, et al. Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function. FASEB J. 2009;23:3361–3367.

 PubMed Web of Science ®Google Scholar