Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such, new treatments are needed to protect the myocardium against the damaging effects of the acute ischaemia and reperfusion injury (IRI) that occurs in AMI, in order to reduce myocardial infarct (MI) size, preserve cardiac function, and improve patient outcomes. In this regard, cardiac mitochondria play a dual role as arbiters of cell survival and death following AMI. Therefore, preventing mitochondrial dysfunction induced by acute myocardial IRI is an important therapeutic strategy for cardioprotection. In this article, we review the role of mitochondria as key determinants of acute myocardial IRI, and we highlight their roles as therapeutic targets for reducing MI size and preventing HF following AMI. In addition, we discuss the challenges in translating mitoprotective strategies into the clinical setting for improving outcomes in AMI patients.

Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced I_Kr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects. From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2^S2808 phosphorylation in both Class 1 and 2 iPSC-CMs. Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by β-blockers is feasible and may represent a novel therapeutic option.

Long QT syndrome 2 (LQTS2) caused by missense mutations in hERG channel is clinically associated with abnormally prolonged ventricular repolarization and sudden cardiac deaths. Modelling monogenic arrhythmogenic diseases using human-induced pluripotent stem cells (hiPSCs) offers unprecedented mechanistic insights into disease pathogenesis. We utilized LQTS2-hiPSC-derived cardiomyocytes (CMs) to elucidate pathological changes and to demonstrate reversal of LQTS2 phenotype in a therapeutic intervention using a pharmacological agent, (N-[N-(N-acetyl-l-leucyl)-l-leucyl]-l-norleucine) (ALLN). We generated LQTS2-specific CMs (A561V missense mutation in KCNH2) from iPSCs using the virus-free reprogramming method. These CMs recapitulate dysfunction of hERG potassium channel with diminished I_Kr currents, prolonged repolarization durations, and elevated arrhythmogenesis due to reduced membrane localization of glycosylated/mature hERG. Dysregulated expression of folding chaperones and processing proteasomes coupled with sequestered hERG in the endoplasmic reticulum confirmed trafficking-induced disease manifestation. Treatment with ALLN, not only increased membrane localization of mature hERG but also reduced repolarization, increased I_Kr currents and reduced arrhythmogenic events. Diverged from biophysical interference of hERG channel, our results show that modulation of chaperone proteins could be therapeutic in LQTS2 treatment. Our in vitro study shows an alternative approach to rescue diseased LQTS2 phenotype via corrective re-trafficking therapy using a small chemical molecule, such as ALLN. This potentially novel approach may have ramifications in other clinically relevant trafficking disorders.

Reliance on low tissue penetrating UV or visible light limits clinical applicability of phototherapy, necessitating use of deep tissue penetrating near-infrared (NIR) to visible light transducers like upconversion nanoparticles (UCNPs). While typical UCNPs produce multiple simultaneous emissions for unidirectional control of biological processes, programmable control requires orthogonal non-overlapping light emissions. These can be obtained through doping nanocrystals with multiple activator ions. However, this requires tedious synthesis and produces complicated multi-shell nanoparticles with a lack of control over emission profiles due to activator crosstalk. Herein, we explore cross-relaxation (CR), a non-radiative recombination pathway typically perceived as deleterious, to manipulate energy migration within the same lanthanide activator ion (Er³⁺) towards orthogonal red and green emissions, simply by adjusting excitation wavelength from 980 to 808 nm. These UCNPs allow programmable activation of two synergistic light-gated ion channels VChR1 and Jaws in the same cell to manipulate membrane polarization, demonstrated here for cardiac pacing.

Significance: Myeloperoxidase (MPO) is a heme peroxidase that is primarily expressed by neutrophils. It has the capacity to generate several reactive species, essential for its inherent antimicrobial activity and innate host defense. Dysregulated MPO release, however, can lead to tissue damage, as seen in several diseases. Increased MPO levels in circulation are therefore widely associated with conditions of increased oxidative stress and inflammation. Recent Advances: Several studies have shown a strong correlation between MPO and cardiovascular disease (CVD), through which elevated levels of circulating MPO are linked to poor prognosis with increased risk of CVD-related mortality. Accordingly, circulating MPO is considered a “high-risk” biomarker for patients with acute coronary syndrome, atherosclerosis, heart failure, hypertension, and stroke, thereby implicating MPO as a multifaceted target for cardiovascular protection. Consistently, recent studies that target MPO in animal models of CVD have demonstrated favorable outcomes with regard to disease progression. Critical Issues: Although most of these studies have established a critical link between circulating MPO and worsening cardiac outcomes, the mechanisms by which MPO exerts its detrimental effects in CVD remain unclear. Future Directions: Elucidating the mechanisms by which elevated MPO leads to poor prognosis and, conversely, investigating the beneficial effects of therapeutic MPO inhibition on alleviating disease phenotype will facilitate future MPO-targeted clinical trials for improving CVD-related outcomes.