Table 1.

Therapeutic targets for regeneration of electrical and mechanical properties of MI scar tissue.

Target	Targeting strategy	Stage	Findings l	Mode	References
Connexin 40, 43	Adenovirus; engraftment of cells expressing Cx43	Preclinical	Enhanced atrial conduction, prevented atrial fibrillation, reduced arrhythmia susceptibility, faster CV through ventricular border zone	Pig, mouse	[11,133–135]
Connexin 43	Mimeticpeptides: αCT1, Gap19/26/27	Preclinical	Reduce arrhythmia incidence and severity, increased CV through IBZ, Cx43 maintained at IDs; Decreased infarct size; inhibit electrical coupling and/or hemichannel activity	Mouse, rat	[141,143,144,146]
Connexin 32	Adenovirus	Preclinical	Increased GJIC, no change in arrhythmia incidence, increased infarct size	Dog	[138]
miR-1	Antagomir	Preclinical	Decreased arrhythmogenesis	Rat	[140]
Cardiac sodium channel 4a (SCN4a)	Adenovirus	Preclinical	Reduced arrhythmia inducibility, increased CV through border zone	Dog	[150]
Sarcoplasmic reticulum calcium-ATPase 2a (SERCA2a)	Adeno-associated virus	Preclinical	Fewer spontaneous premature ventricular contractions and spontaneous or induced non-sustained VT episodes, fewer spontaneous SR calcium release events, reduced total SR calcium leak, fewer triggered arrhythmias	Rat, Sheep	[153]
Sarcoplasmic reticulum calcium-ATPase 2a (SERCA2a)	Adeno-associated virus	Clinical, Phase II	Decreased incidence of ventricular arrhythmias and triggers, improved arrhythmogenic substrate	Human	[155,156]
KCNH2-G628S	Adenovirus	Preclinical	Increased APD; prolonged refractory period, extending the reentrant wavelength and preventing arrhythmias	Pig	[158]
Potassium channel (Kv1.3, Kir2.1)	Engraftment of Kv1.3- and Kir2.1-expressing fibroblasts	Preclinical	Prolonged local refractory period, engrafted cells coupled with myocytes leading to reduced automaticity and prolonged refractoriness	Rat, Pig	[159]
Semaphorin 3a	Adenovirus	Preclinical	Increased levels of potassium channels at the border zone	Rat	[160]
Endothelin	ET-1 antagonists	Preclinical, Clinical	Cardioprotective effects; no improvements in cardiac remodeling in clinical trials, but also no adverse effects	Rat, Human	[180–184]
Angiotensin II pathway	Ang-II inhibition	Preclinical, Clinical	Decreased interstitial fibrosis, increased CV, and increased GJ conductance	Hamster, Human	[185,186]
Interleukin-1	IL-1 inhibition	Preclinical, Clinical	Attenuated LV remodeling, preserved cardiac function, allowed normal infarct healing	Mouse, Human	[190–193]
TGF-β pathway	TGF-β inhibition	Preclinical	Reduced fibrosis and progression to heart failure in a model of pressure overload	Mouse	[195]
MMP	Broad spectrum MMP inhibition; targeted MMP inhibition	Preclinical	Overall collagen area of MI scar changes very little with broad spectrum inhibition, but did limit LV dilation, reduced myocyte hypertrophy in non-infarcted regions, decreased tissue and chamber compliance; No significant changes in collagen content in targeted reduction or transgenic knockouts of MMP-1, -3, -9, -12, and MT1-MMP	Mouse, Rat, Pig	[197–203]
Wnt pathway	Wnt pathway transgenics or interfering peptides	Preclinical	Reduced MMP level and leukocyte infiltration, decreased scar size, improved cardiac function, reduced fibrosis, reduced infarct expansion and development of heart failure	Mouse	[222–224]
Fibroblast density	NA	Modeling	At high density, fibroblasts cause resting depolarization and block propagation, protecting against arrhythmias	In silico	[226]
Scar stiffness	Scar anisotropy	Modeling, Preclinical	Increasing stiffness of isotropic infarct tissue does not alter LV pump function of the heart, stiffening scar in longitudinal direction (or longitudinal mechanical restraint) increases pump function	In silico, Dog	[12,233,234]
Scar stiffness	Intra-scar polymer injection	Preclinical, Modeling	Maintained fractional shortening and wall thickness; Stiff polymers improve cardiac mechanics; Injections into IBZ at multiple locations is most beneficial, while injections into scar produce mixed results on cardiac pressure-volume relationships	Rat, Sheep, In silico	[234,236–238]
Increase scar stiffness by increasing collagen content	Inhibiting MMPs or increasing TIMPs by hydrogel or adenoviral delivery	Preclinical	Reduced MMP activity and LV remodeling, increased fibrillary collagen content and LV ejection fraction	Mouse, Pig	[239–241]