Real-time Pressure-volume Analysis of Acute Myocardial Infarction in Mice

Acute myocardial infarction can lead to acute heart failure and cardiogenic shock. The evaluation of hemodynamics is critical for the evaluation of any ...

University Hospital Essen

Following successful resuscitation from cardiac arrest (CA), neurological impairment and other types of organ dysfunction cause significant morbidity and mortality-a condition termed post-cardiac arrest syndrome. Whole-body ischemia/reperfusion with oxygen debt activates immunologic and coagulation pathways increasing the risk of multiple organ failure and infection. We here examined the role of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) in post-cardiac arrest syndrome.

MIF reflects tissue damage rather than inflammation in post-cardiac arrest syndrome in a real life cohort.

Diastolic dysfunction is highly prevalent, and ageing is the main contributor due to impairments in active cardiac relaxation, ventriculo-vascular stiffening, and endothelial dysfunction. Nitric oxide (NO) affects cardiovascular functions, and NO bioavailability is critically reduced with ageing. Whether replenishment of NO deficiency with dietary inorganic nitrate would offer a novel approach to reverse age-related cardiovascular alterations was not known.

Impact of dietary nitrate on age-related diastolic dysfunction.

Although urgently needed in clinical practice, a cardioprotective therapeutic approach against myocardial ischemia/ reperfusion injury remains to be established. Remote ischemic preconditioning (rIPC) and ischemic preconditioning (IPC) represent promising tools comprising three entities: the generation of a protective signal, the transfer of the signal to the target organ, and the response to the transferred signal resulting in cardioprotection. However, in light of recent scientific advances, many controversies arise regarding the efficacy of the underlying signaling. We here show methods for the generation of the signaling cascade by rIPC as well as IPC in a mouse model for  myocardial ischemia/ reperfusion injury using highly reproducible approaches. This is accomplished by taking advantage of easily applicable preconditioning strategies compatible with the clinical setting. We describe methods for using laser Doppler perfusion imaging to monitor the cessation and recovery of perfusion in real time. The effects of preconditioning on cardiac function can also be assessed using ultrasound or magnetic resonance imaging approaches. On a cellular level, we confirm how tissue injury can be monitored using histological assessment of infarct size in conjunction with immunohistochemistry to assess both aspects in a single specimen. Finally, we outline, how the rIPC-associated signaling can be transferred to the target cell  conservation of the signal in the humoral (blood) compartment. This compilation of experimental protocols including a conditioning regimen comparable to the clinical setting should proof useful to both beginners and experts in the field of myocardial infarction, supplying information for the detailed procedures as well as troubleshooting guides.

A practical approach to remote ischemic preconditioning and ischemic preconditioning against myocardial ischemia/reperfusion injury.

Acute myocardial infarction is the leading cause of mortality in the industrialized world. While it is essential to attempt an early reperfusion of ischemic myocardial territories, reperfusion itself adds damage to the heart, the ischemia-reperfusion (I/R) injury. Particularly the injury resulting from the very first minutes of reperfusion remains incompletely understood. MicroRNAs (miRNAs) are dynamic regulators in I/R injury. Nitric oxide (•NO) signaling, in turn, interacts with miRNA signaling. Our previous investigations showed that •NO signaling in I/R could be modulated by nitrite. We therefore sought to investigate the role of miRNAs in nitrite cardioprotection with focus on the first few minutes of reperfusion. The study was conducted in mice in vivo with 30 min of ischemia and 5 min of reperfusion. Mice received a single-dose of nitrite or saline intracardially 5 min prior to reperfusion. We identified nine miRNAs to be up-regulated after 5 min of reperfusion. The up-regulation of almost half of those miRNAs (miR-125a-5p, miR-146b, miR-339-3p, miR-433) was inhibited by nitrite treatment, perpetuating baseline values. In silico analysis revealed the Irak-M gene to be a target of miR-146b and miR-339-3p. Correspondingly, a rise in Irak-M transcript and protein levels occurred by nitrite treatment within the early phase of reperfusion. The results demonstrate that already a very short phase of reperfusion is sufficient for significant dysregulation in cardiac miRNAs expression and that nitrite preserves baseline values of miRNAs in the scale of only a few minutes. These findings hint at a potential novel cardioprotective mechanism of nitrite signaling.

Inorganic nitrite modulates miRNA signatures in acute myocardial in vivo ischemia/reperfusion.

Risk assessment in patients with acute coronary syndromes (ACS) is critical in order to provide adequate treatment. We performed a systematic meta-analysis to assess the predictive role of serum C-reactive protein (CRP) in patients with ST-segment elevation myocardial infarction (STEMI), treated with primary percutaneous coronary intervention (PPCI). We included 7 studies, out of 1,033 studies, with a total of 6,993 patients with STEMI undergoing PPCI, which were divided in the high or low CRP group, according to the validated cut-off values provided by the corresponding CRP assay. High CRP values were associated with increased in-hospital and follow-up all-cause mortality, in-hospital and follow-up major adverse cardiac events (MACE), and recurrent myocardial infarction (MI). The pre-procedural CRP predicted in-hospital target vessel revascularization (TVR), but was not associated with acute/subacute and follow-up in-stent restenosis (ISR), and follow-up TVR. Thus, pre-procedural serum CRP could be a valuable predictor of global cardiovascular risk, rather than a predictor of stent-related complications in patients with STEMI undergoing PPCI. This biomarker might have the potential to improve the management of these high-risk patients.

Preprocedural C-Reactive Protein Predicts Outcomes after Primary Percutaneous Coronary Intervention in Patients with ST-elevation Myocardial Infarction a systematic meta-analysis.

Continuous contractile activity of the heart is essential and the required energy is mostly provided by fatty acid (FA) oxidation. Myocardial lipid accumulation can lead to pathological responses, however the underlying mechanisms remain elusive. The role of myoglobin in dioxygen binding in cardiomyocytes and oxidative skeletal muscle has widely been appreciated. Our recent work established myoglobin as a protector of cardiac function in hypoxia and disease states. We here unravel a novel role of cardiac myoglobin in governing FA metabolism to ensure the physiological energy production through β-oxidation, preventing myocardial lipid accumulation and preserving cardiac functions. In vivoH magnetic resonance spectroscopy unveils a 3-fold higher deposition of lipids in mouse hearts lacking myoglobin, which was associated with depressed cardiac function compared to wild-type hearts as assessed by echocardiography. Mass spectrometry reveals a marked increase in tissue triglycerides with preferential incorporation of palmitic and oleic acids. Phospholipid levels as well as the metabolome, transcriptome and proteome related to FA metabolism tend to be unaffected by myoglobin ablation. Our results reveal a physiological role of myoglobin in FA metabolism with the lipid accumulation-suppressing effects of myoglobin preventing cardiac lipotoxicity.

A novel physiological role for cardiac myoglobin in lipid metabolism.

Myocardial infarction remains the single leading cause of death worldwide. Upon reperfusion of occluded arteries, deleterious cellular mediators particularly located at the mitochondria level can be activated, thus limiting the outcome in patients. This may lead to the so-called ischemia/reperfusion (I/R) injury. Calpains are cysteine proteases and mediators of caspase-independent cell death. Recently, they have emerged as central transmitters of cellular injury in several cardiac pathologies e.g. hypertrophy and acute I/R injury.

S-nitrosation of calpains is associated with cardioprotection in myocardial I/R injury.

Cardioprotective strategies to prevent damage to mitochondria in acute myocardial infarction are warranted to reduce lethal myocardial ischemia/reperfusion (I/R) injury. Mitochondrial antagonists in I/R are reactive oxygen species (ROS), deteriorated calcium signaling, permeabilization of the mitochondrial outer membrane (MOM) and deranged mitochondrial structural dynamism (fusion and fission). Nitric oxide (NO) related signaling can protect hearts from I/R. Albeit the underlying signaling is incompletely resolved, recent data point to a particular involvement of protective posttranslational modification of mitochondrial elements. We and others have demonstrated that hypoxic NO signaling in cardiomyocytes is associated with a posttranslational mitochondrial complex I modification to reduce the burden of ROS. Induction of cardioprotective NO signaling may occur through several pathways. These include (i) the supplementation with mitochondria unspecific and specific NO-donors, (ii) the administration of the 'hypoxic-NO donors nitrate and nitrite' and (iii) the enhancement of endogenous NO formation, e.g. by remote ischemic preconditioning maneuvers (rIPC). In this chapter, we outline how NO signaling is activated in the cardiomyocyte, characterize the downstream signaling pathways and discuss how this could translate into a tractable therapeutic approach in patients requiring cardioprotection.

Nitrite-Nitric Oxide Signaling and Cardioprotection.

Cardiomyocytes consist of longitudinally oriented myofibril bundles with a misaligned composition caused by the uneven contours of the intercalated discs. The cytoplasmic space harbors the organelles, including mitochondria. This study investigated whether cardiomyocytes contain spatially and ultrastructurally discrete pools of mitochondria that can be separated for structurally and functionally appraisal in (patho)physiology. Transmission electron microscopy disclosed continuous transitions of mitochondria without attributable characteristics from beneath the sarcolemma directly into the barrier-free cytoplasmic space between myofibrils. The various shapes and sizes of mitochondria are formed by myofibril positioning and the space available independent of their localization within the cardiomyocytes. Furthermore, the established enzymatic isolation procedure including proteinase treatment resulted in loss of mitochondrial proteins, as evidenced by immunogold labeling of Connexin43 in situ, a postulated marker for distinguishing mitochondrial subpopulations. Moreover, mitochondrial ATP produced in those mitochondria was not different. These findings preclude a spatial and ultrastructural grading of cardiac mitochondria and their distinct separation and classification in subsarcolemmal and interfibrillar subpopulations.

Mouse cardiac mitochondria do not separate in subsarcolemmal and interfibrillar subpopulations.

The monoclonal antibody bevacizumab effectively inhibits angiogenesis in several types of cancers by blocking vascular endothelial growth factor. However, life-threatening cardiovascular adverse effects could limit its use and may warrant specific follow-up strategies.

Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20 000 Patients.

The pulsed electron avalanche knife (PEAK) PlasmaBlade™ is an innovative electrosurgical device that uses a novel technology to cut tissues. It has been proven to be safe and feasible in ear, nose, and throat surgery, but there are only limited data concerning the use of PlasmaBlade™ instead of conventional electrocautery in cardiac implantable electronic device (CIED) procedures except for generator replacements.

Pulsed electron avalanche knife (PEAK) PlasmaBlade™ in pacemaker and defibrillator procedures.

BACKGROUND Following acute coronary intervention in cardiology patients, the combined medical therapy with the platelet inhibitory drug ticagrelor and a statin medication (e.g., simvastatin) is recommended according to international guidelines. Yet combined therapeutic regimens have the potential of pharmacological interaction with both ticagrelor and simvastatin being metabolized by CYP3A4. Rhabdomyolysis is a known side-effect of statin therapy and combined therapy increases the susceptibility to this complication. CASE REPORT A 72-year-old patient presented to our Emergency Department with typical signs of rhabdomyolysis consisting of muscular cramps and pain in both legs and a significant elevation of creatinine kinase (CK). Five months prior to this presentation, he had been hospitalized due to acute coronary syndrome followed by a coronary intervention of a high-grade left anterior descending artery stenosis. His long-term medication included simvastatin 20 mg daily, which he had taken for several years, and ticagrelor, which had been added to his medication following coronary intervention. The patient showed fast recovery of symptoms and rapid normalization of CK levels upon treatment change from ticagrelor to clopidogrel with a paused statin administration. CONCLUSIONS The combined use of ticagrelor with low dose simvastatin poses a risk for rhabdomyolysis even in patients with normal kidney function. Patients treated with ticagrelor might require changes in statin therapy and dose adjustments in order to avoid pharmacological interactions and higher risk for adverse effects.

Ticagrelor Leads to Statin-Induced Rhabdomyolysis: A Case Report.

Background Targeted therapy with tyrosine kinase inhibitors with anti-vascular endothelial growth factor activity improves survival of cancer patients. Cardiovascular complications are critical and it is unknown whether these require specific treatment strategies. We aimed to clarify the associated risk of cardiovascular adverse events in patients treated with tyrosine kinase inhibitors. Design The design of this study was a meta-analysis of randomised controlled trials. Methods We searched PubMed, Cochrane, EMBASE and Web of Science databases for randomised controlled trials published until January 2017 that assessed patients with different types of cancer treated with or without tyrosine kinase inhibitors in addition to standard chemotherapy. Results A total of 29,252 patients from 71 randomised controlled trials were included. Tyrosine kinase inhibitor treatment was associated with a higher cardiac ischaemia relative risk (relative risk = 1.69; 95% confidence interval: 1.12-2.57; p = 0.01), with the highest risks observed for sorafenib and patients with renal cancer. Risk of thrombocytopaenia (relative risk = 2.2; 95% confidence interval: 1.73-2.79; p < 0.001) was highest for regorafenib and patients with breast cancer. Left ventricular systolic dysfunction was increased after tyrosine kinase inhibitor therapy (relative risk = 2.53; 95% confidence interval:1.79 - 3.57; p < 0.001), with the highest risks reported for sunitinib and hepatocellular cancer. QT corrected interval prolongation (relative risk = 6.25; 95% confidence interval: 3.44-11.38; p < 0.001) and arterial hypertension (relative risk = 3.78; 95% confidence interval: 3.15-4.54; p < 0.001) were reported. The relative risks of arterial adverse events, cerebral ischaemia, venous adverse events and pulmonary embolism were similar across groups. Conclusion Tyrosine kinase inhibitors increase the risk of severe cardiovascular and particularly thrombotic adverse events. Specific treatment regimens when prescribing tyrosine kinase inhibitor therapies appear desirable.

Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: A meta-analysis of approximately 29,000 cancer patients.

Matthias Totzeck

West German Heart and Vascular Center,
Department of Cardiology and Vascular Medicine,
Medical Faculty,
West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Medical Faculty

University Hospital Essen

Real-time Pressure-volume Analysis of Acute Myocardial Infarction in Mice

Matthias Totzeck

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}West German Heart and Vascular Center,Department of Cardiology and Vascular Medicine,Medical Faculty,West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Medical Faculty

University Hospital Essen

Real-time Pressure-volume Analysis of Acute Myocardial Infarction in Mice

West German Heart and Vascular Center,
Department of Cardiology and Vascular Medicine,
Medical Faculty,
West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, Medical Faculty