Novel therapeutics in myocardial infarction: targeting microvascular dysfunction and reperfusion injury

Fordyce, Christopher B.; Gersh, Bernard J.; Stone, Gregg W.; Granger, Christopher B.

doi:10.1016/j.tips.2015.06.004

Cited by 55 publications

(45 citation statements)

References 140 publications

(147 reference statements)

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“…In present study, we also found that the pericyte coverage was decreased in the heart of SIRT3 KO mice at both normal and ischemic conditions, indicating a possibly active role of pericyte during ischemia. A “no-reflow” phenomenon that can be described as inability to reperfusion an ischemic area has been confirmed by many studies [3;7;41]. Most recently clinical studies have demonstrated that dying pericytes that irreversibly constrict capillaries might be the major cause of this phenomenon [42].…”

Section: Discussionmentioning

confidence: 99%

“…Coronary microvascular dysfunction has been shown to be highly prevalent in post-MI patients, and is associated with poor prognosis regardless of successful reopening of epicardial vessel [3]. Coronary microvascular dysfunction has been described in many cardiac disease associated with aging, diabetes and hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…MI results in left ventricle dysfunction and subsequent heart failure, which is the leading cause of death in the USA [1;2]. Mitochondrial dysfunction, oxidative stress, disrupted calcium homeostasis and cellular metabolism contribute to MI injury [3]. MI activates a series of endogenous protective mechanisms including myocardial angiogenesis in the ischemic area of MI that depends on endothelial function and promotes collateral vessel formation, to maintain basic cardiac function, homeostasis and recovery [4].…”

Section: Introductionmentioning

confidence: 99%

“…Although the door-to-balloon time declined significantly in patients receiving PCI, in-hospital mortality remained unchanged [6]. Coronary flow reserve (CFR) is widely used as a marker of coronary microvascular dysfunction which has been shown to increase the risk of cardiovascular events and is associated with increased MI size, reduced left ventricle (LV) ejection fraction, adverse LV remodeling, and reduced long-term survival [3]. Advanced age, hypertension and diabetes usually have pre-existing coronary microvascular dysfunction [5;7].…”

Section: Introductionmentioning

confidence: 99%

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Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Zeng

Chen

2016

International Journal of Cardiology

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Rationale Sirtuin (SIRT3), a major nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase in mitochondria, declines with aging and its ablation is associated with accelerated development of cardiovascular diseases. However, the role of SIRT3 in coronary microvascular function and post-MI recovery has not been incompletely understood. Objective The goal was to investigate whether ablation of SIRT3 causes coronary microvascular dysfunction, exacerbates post-myocardial ischemia (MI) cardiac dysfunction and impairs cardiac recovery. Methods and results Using endothelial cells (ECs) isolated from SIRT3 knockout (KO) mice, we revealed that the angiogenic capabilities were significantly reduced in SIRT3 deficient ECs. SIRT3 KO mice presented a pre-existing coronary microvascular dysfunction and microvascular rarefaction, as evidenced by a reduction in hyperemic peak diastolic blood flow velocity and coronary flow reserve (CFR), accompanied by loss of capillary-pericytes in the heart. Furthermore, SIRT3 KO mice subjected to myocardial ischemia by the ligation of left anterior descending coronary artery (LAD) exhibited more severe cardiac dysfunction together with decreased pericyte/EC coverage than that of WT mice. In contrast, overexpression of SIRT3 preserved cardiac function in post-MI mice. Immunoblot analysis further showed that the expression of angiopoietin-1 (Ang-1), vascular endothelial growth factor (VEGF) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were significantly decreased in the SIRT3-deficient ischemic hearts than those of WT ischemic hearts. This was accompanied by higher levels of cleaved caspase-3 and apoptosis. Conclusion Our results reveal a potential mechanism by which SIRT3 deletion exacerbates post-MI cardiac dysfunction and impairment of cardiac recovery involving microvascular rarefaction and pre-existing coronary microvascular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Zeng

Chen

2016

International Journal of Cardiology

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“…In their article, Fordyce et al review a large number of novel therapies in myocardial infarction [1]. The review article is very interesting; however, we would like to point out that there are new agents that show promise in initial proof-of-principle clinical studies in patients with ST-segment elevation myocardial infarction (STEMI).…”

mentioning

confidence: 99%

Novel Cardioprotective Agents: Fact or Fiction?

Abreu-González

2015

Trends in Pharmacological Sciences

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Evaluation of intracoronary hyperoxemic oxygen therapy in acute anterior myocardial infarction: The IC‐HOT study

David

Khan

Patel

et al. 2018

Cathet Cardio Intervent

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Background In the randomized AMIHOT‐II trial, supersaturated oxygen [SSO2] delivered into the left anterior descending (LAD) artery via an indwelling intracoronary infusion catheter following primary percutaneous coronary intervention (PCI) significantly reduced infarct size in patients with anterior ST‐segment elevation myocardial infarction (STEMI) but resulted in a numerically higher incidence of safety events. Objectives The IC‐HOT study evaluated the safety of SSO2 therapy selectively delivered to the left main coronary artery (LMCA) for 60 minutes after PCI in patients with anterior STEMI. Methods SSO2 therapy was administered to the LMCA after stent implantation in 100 patients with anterior STEMI and proximal or mid‐LAD occlusion presenting within 6 hours of symptom onset. The primary endpoint was the 30‐day composite rate of net adverse clinical events (NACE) (death, reinfarction, clinically driven target vessel revascularization, stent thrombosis, severe heart failure, or TIMI major/minor bleeding) compared against an objective performance goal of 10.7%. Cardiac magnetic resonance imaging was performed at 4 and 30 days to assess infarct size. Results SSO2 delivery was successful in 98% of patients. NACE at 30 days occurred 7.1% of patients (meeting the primary safety endpoint of the study); there were no deaths, only one stent thrombosis and one case of severe heart failure. Median [interquartile range] infarct size was 24.1% [14.4%, 31.6%] at 4 days and 19.4% [8.8%, 28.9%] at 30 days. Conclusion Following primary PCI in acute anterior STEMI, infusion of SSO2 via the LMCA was feasible and was associated with a favorable early safety profile.

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Novel therapeutics in myocardial infarction: targeting microvascular dysfunction and reperfusion injury

Cited by 55 publications

References 140 publications

Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia

Novel Cardioprotective Agents: Fact or Fiction?

Evaluation of intracoronary hyperoxemic oxygen therapy in acute anterior myocardial infarction: The IC‐HOT study

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