Remote ischemic conditioning to protect the heart in myocardial infarction : therapeutic intervention and underlying mechanisms

Background Urgent reperfusion of the occluded coronary artery halts the ischemic insult to the myocardium and is the single most important action to limit infarct size in ST-elevation myocardial infarction. However, reperfusion itself introduces an additional threat to the recovering ischemic myocardium whereby still viable cardiomyocytes suffer additional irreversible damage. This is referred to as reperfusion injury and significantly contributes to final infarct size. As of yet there is no established treatment to avoid or limit reperfusion injury, but promising results have been presented from early clinical trials of remote ischemic conditioning, whereby short cycles of non-harmful ischemia and reperfusion performed in remote tissue during the late stages of myocardial ischemia or early stages of myocardial reperfusion elicits an innate mechanism that ultimately terminates in cardioprotection. However, the exact underlying mechanisms are not fully known and additional clinical trials are needed to decide the possible role for remote ischemic conditioning in the treatment of patients with ST-elevation myocardial infarction. This thesis was undertaken to determine the effects of remote ischemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction and to explore underlying mechanisms. Studies I and II The effect of remote ischemic conditioning performed during the late stages of ischemia and at reperfusion as an adjunct to primary percutaneous intervention was investigated in 115 patients with anterior ST-elevation myocardial infarction. Infarct size as evaluated by cardiac magnetic resonance imaging during the first week and six months after the myocardial infarction, as well as clinical outcomes up to three years of follow-up were not affected by remote ischemic conditioning. Study III The involvement of the glucagon-like peptide-1 receptor in the signaling pathway of remote ischemic conditioning was explored in twelve healthy males. Intravenous infusion of the glucagon-like peptide-1 receptor antagonist exendin(9-39) abolished the protection against endothelial ischemia-reperfusion injury provided by remote ischemic conditioning, as evaluated by ultrasound based measurement of flow mediated dilatation in the brachial artery. Study IV The effect of chronic ticagrelor treatment on endothelial function was evaluated in twenty male patients with a previous acute coronary syndrome. Chronic ticagrelor treatment was not associated with protection against endothelial ischemia-reperfusion injury or better basal endothelial function compared to after its discontinuation, as evaluated by ultrasound based measurement of flow mediated dilatation in the brachial artery. Conclusions Remote ischemic conditioning performed during the late stages of ischemia and at reperfusion as an adjunct to primary percutaneous coronary intervention in patients with anterior STelevation myocardial infarction does not lead to smaller myocardial infarct size or improved clinical outcomes. Remote ischemic conditioning utilizes a glucagon-like peptide-1 receptor dependent pathway to protect against endothelial ischemia-reperfusion injury. Chronic ticagrelor treatment does not provide protection against endothelial ischemia-reperfusion injury or improved basal endothelial function compared to after its discontinuation

Same-day discharge after percutaneous closure of persistent foramen ovale using intracardiac echocardiography and the Gore Septal Occluder

AimPeriprocedural and postinterventional care of patients undergoing closure of patent foramen ovale (PFO) varies significantly across care providers. Same-day discharge (SDD) after transcatheter interventions is an evolving concept. This study aimed to assess the same-day discharge rate and incidence of complications in patients undergoing PFO closure with intracardiac echocardiography (ICE) using the Gore®Cardioform Septal Occluder (GSO) device. The secondary aim was to analyse the efficacy of femoral vein closure with Perclose ProGlide.MethodsPatients who underwent PFO closure with the GSO device at a university hospital in Stockholm, Sweden, were retrospectively included between March 1, 2017, and June 30, 2020, all with cryptogenic stroke as the indication for the procedure. All patients underwent PFO closure with conscious sedation and local anaesthesia. The indication for all patients was a cryptogenic stroke. Periprocedural imaging was performed using ICE and fluoroscopy in all patients. Patient characteristics and periprocedural data were collected from patient charts. Patients were kept on bed rest for 4–6 h post-intervention. Transthoracic echocardiography and clinical examination, including groin status, were performed before discharge. No clinical routine follow-up was performed the day following the intervention. Clinical follow-up was done by phone call two weeks after the procedure, and echocardiographic follow-up was done after 12 months. Data were analysed using linear and logistic regression models.ResultsIn total, 262 patients were included, of which 246 (94%) had SDD. 166 patients (63%) received the ProGlide™ system for femoral vein access closure. Post-procedural arrhythmias occurred in 17 (6%) patients, and vascular complications in 9 patients (3%). The overall closure rate at follow-up was 98.5%. 25 out of 264 patients (9.5%) had to be readmitted within the first eight weeks after PFO closure, 16 due to atrial fibrillation warranting electric cardioversion, one due to an arteriovenous fistula that was operated, four due to chest pain/pain at the access site, and four patients developed fever. There was no difference in SDD among patients who received ProGlide™ vs. patients who did not receive ProGlide™.ConclusionSDD appears safe after transcatheter PFO closure with the GSO device with high procedural success rates. Low rates of complications and readmissions make the intervention suitable for this patient-friendly and cost-effective concept

Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart

Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury. During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic - however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial ischaemia/reperfusion injury

Remote ischemic conditioning to protect the heart in myocardial infarction : therapeutic intervention and underlying mechanisms [Elektronisk resurs]

Background: Urgent reperfusion of the occluded coronary artery halts the ischemic insult to the myocardium and is the single most important action to limit infarct size in ST-elevation myocardial infarction. However, reperfusion itself introduces an additional threat to the recovering ischemic myocardium whereby still viable cardiomyocytes suffer additional irreversible damage. This is referred to as reperfusion injury and significantly contributes to final infarct size. As of yet there is no established treatment to avoid or limit reperfusion injury, but promising results have been presented from early clinical trials of remote ischemic conditioning, whereby short cycles of non-harmful ischemia and reperfusion performed in remote tissue during the late stages of myocardial ischemia or early stages of myocardial reperfusion elicits an innate mechanism that ultimately terminates in cardioprotection. However, the exact underlying mechanisms are not fully known and additional clinical trials are needed to decide the possible role for remote ischemic conditioning in the treatment of patients with ST-elevation myocardial infarction. This thesis was undertaken to determine the effects of remote ischemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction and to explore underlying mechanisms. Studies I and II: The effect of remote ischemic conditioning performed during the late stages of ischemia and at reperfusion as an adjunct to primary percutaneous intervention was investigated in 115 patients with anterior ST elevation myocardial infarction. Infarct size as evaluated by cardiac magnetic resonance imaging during the first week and six months after the myocardial infarction, as well as clinical outcomes up to three years of follow-up were not affected by remote ischemic conditioning. Study III: The involvement of the glucagon-like peptide-1 receptor in the signaling pathway of remote ischemic conditioning was explored in twelve healthy males. Intravenous infusion of the glucagon-like peptide-1 receptor antagonist exendin(9-39) abolished the protection against endothelial ischemia-reperfusion injury provided by remote ischemic conditioning, as evaluated by ultrasound based measurement of flow mediated dilatation in the brachial artery. Study IV: The effect of chronic ticagrelor treatment on endothelial function was evaluated in twenty male patients with a previous acute coronary syndrome. Chronic ticagrelor treatment was not associated with protection against endothelial ischemia-reperfusion injury or better basal endothelial function compared to after its discontinuation, as evaluated by ultrasound based measurement of flow mediated dilatation in the brachial artery. Conclusions: Remote ischemic conditioning performed during the late stages of ischemia and at reperfusion as an adjunct to primary percutaneous coronary intervention in patients with anterior ST-elevation myocardial infarction does not lead to smaller myocardial infarct size or improved clinical outcomes. Remote ischemic conditioning utilizes a glucagon-like peptide-1 receptor dependent pathway to protect against endothelial ischemia-reperfusion injury. Chronic ticagrelor treatment does not provide protection against endothelial ischemia-reperfusion injury or improved basal endothelial function compared to after its discontinuation

Remote ischemic conditioning fails to protect against ischemia-reperfusion injury in patients with untreated familial hypercholesterolemia

Abstract Background/Introduction Remote ischemic conditioning (RIC) is the action of brief periods of ischemia to a remote tissue and has been suggested to protect against myocardial ischemia-reperfusion (IR) injury. The outcomes of clinical trials in terms of clinical endpoints and infarct size reduction have been variable, which may be related to influence of comorbidities on the effect of RIC. Animal studies suggest that hypercholesterolemia attenuates the cardioprotective effect of RIC, but no data from study on patients are available. Hence, our aim was to investigate the response of RIC on IR-induced endothelial dysfunction in patients with familial hypercholesterolemia (FH). Purpose To investigate if RIC protects against endothelial dysfunction induced by IR in patients with FH with high (≥5.5 mmol/L) and low (≤2.5 mmol/L) LDL-cholesterol levels. Methods All subjects with FH (n=12) with LDL ≥5.5 mmol/L, FH with LDL &amp;lt;2.5 mmol/L (n=12), and age-matched healthy control subjects (n=12) participated in two protocols separated by at least one week. In both protocols, endothelium-dependent vasodilatation was assessed by determination of flow-mediated vasodilatation (FMD) of the brachial artery at baseline and again after 20 minutes of forearm ischemia and 20 minutes of reperfusion. Forearm ischemia was induced by inflating a blood pressure cuff on the upper arm to 200 mmHg. An additional inflatable cuff was placed around the left thigh. In one protocol (IR+sham), this cuff was left uninflated. In the second protocol (IR+RIC), it was inflated to 200 mmHg in four cycles of 5 minutes inflation and 5 min deflation with the first cycle starting at the onset of forearm ischemia. Results Plasma mean LDL-cholesterol was significantly higher in the FH group with high LDL (6.6±1.4 mmol/L) compared to the control group (2.4±0.7 mmol/L; p&amp;lt;0.01) and the low LDL FH group (2.0±0.6 mmol/L; p&amp;lt;0.001). FMD was markedly reduced (p&amp;lt;0.05) in all subjects following IR+sham, indicating IR-induced endothelial dysfunction in all three groups. As expected, RIC prevented the reduction in FMD after IR in the control group (Fig 1). By contrast, in the FH group with high LDL, RIC failed to protect from IR-induced endothelial dysfunction. Thus, in this group the decrease in FMD was similar after IR+RIC and IR+ sham (Fig 1). In the FH group with LDL &amp;lt;2.5 mmol/L, the decrease in FMD induced by IR was attenuated by RIC (p=0.05). Conclusion These observations suggest that RIC, which protects from IR-induced endothelial dysfunction in healthy controls, fails to protect from IR-induced endothelial dysfunction in patients with FH and LDL-cholesterol &amp;gt;5.5 mmol/L. The protective effect of RIC is restored after treatment of hypercholesterolemia. This finding may have bearings on the clinical efficacy of RIC in patients with ST-elevation myocardial infarction. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Heart-lung foundation </jats:sec

Ticagrelor Does Not Protect Against Endothelial Ischemia-Reperfusion Injury in Patients With Coronary Artery Disease

Background: Ticagrelor is a recommended P2Y12 receptor inhibitor after acute coronary syndrome (ACS). Its superiority has been suggested to rely on pleiotropic effects beyond platelet inhibition. Experimental studies indicate that ticagrelor may protect from ischemia-reperfusion injury but no data are available from such studies on patients. This study aimed to determine if chronic ticagrelor treatment protects against endothelial ischemia-reperfusion injury in patients with a previous ACS. Methods: Patients with a previous ACS were studied with flow mediated dilatation of the left brachial artery to determine the degree of endothelial ischemia-reperfusion injury before and after discontinuation of ticagrelor treatment, which had been continuous since 1 year. Each patient underwent 3 identical examinations. The first examination (Visit A) was at the end of ticagrelor treatment and the following 2 (Visit B and C) were after cessation of this treatment with an interval of 2 to 4 weeks. Results: Ischemia and reperfusion induced significant impairment of endothelial function at all 3 occasions (absolute decline in flow mediated dilatation 3.0% ± 0.7 at Visit A ( P &lt; 0.001), 1.9% ± 0.9 at Visit B ( P &lt; 0.05) and 1.9% ± 0.4 at Visit C ( P &lt; 0.0001)). However, there was no difference in the degree of endothelial ischemia-reperfusion injury or baseline endothelial function between the visits. Conclusion: Chronic ticagrelor treatment in patients 1 year after an ACS does not protect against endothelial ischaemia-reperfusion injury. Nor is it associated with better basal endothelial function compared to after discontinuation of treatment. </jats:sec