Abstract The damage inflicted on the myocardium during acute myocardial infarction is the result of 2 processes: ischemia and subsequent reperfusion (ischemia/reperfusion injury). During the last 3 ...decades, therapies to reduce ischemic injury (mainly reperfusion strategies) have been widely incorporated into clinical practice. The remarkable reduction in death rates achieved with these therapies has resulted in a shift in emphasis from efforts to reduce mortality to a focus on tackling the downstream consequence of survival: post-infarction heart failure. Infarct size is the main determinant of long-term mortality and chronic heart failure, and thus, the possibility of limiting the extent of necrosis during an ST-segment elevation myocardial infarction is of great individual and socioeconomic value. After the great success of therapies to reduce ischemic injury, the time has come to focus efforts on therapies to reduce reperfusion injury, but in the recent few years, few interventions have successfully passed the proof-of-concept stage. In this review, we examine the past, present, and future therapies to reduce ischemia/reperfusion injury.
Conventional aortic valve replacement (AVR) remains the therapy of choice for many patients with severe aortic valve disease. The unique German Aortic Valve Registry (GARY) allows the comparison of ...contemporary outcomes of AVR with those of transcatheter AVRs. We report here real-world, all-comers outcomes of AVR, including combined AVR and coronary bypass grafting (AVR+CABG).
A total of 34,063 patients who received AVR (22,107 patients, 39% female; mean age 68.0 ± 11.3 years, mean logistic European System for Cardiac Operative Risk Evaluation, 8.6%) or AVR+CABG (11,956 patients, 28% female; mean age 72.6 ± 7.8 years, mean logistic European System for Cardiac Operative Risk Evaluation, 10.7%) between 2011 and 2013 were analyzed and followed up to assess the 1-year outcome.
In-hospital mortality was 2.3% for AVR and 4.1% for AVR+CABG. Other important outcome variables include stroke (AVR, 1.2%; AVR+CABG, 1.9%) and new pacemaker implantation (AVR, 4.4%; AVR+CABG, 3.6%). Survival at 1 year was 93.2% for AVR and 89.4% for AVR+CABG. Total stroke rates at 1 year were 1.6% for AVR and 2.0% AVR+CABG. Quality of life assessment indicated that most patients were in New York Heart Association Functional Classification I or II (AVR, 86%; AVR+CABG, 84%) and that they were satisfied with the overall postoperative course (AVR, 88%; AVR+CABG, 87%).
Contemporary surgical AVR yields excellent outcomes with low in-hospital mortality, a low overall complication rate, and good 1-year outcome for all risk groups. Accordingly, conventional AVR remains an important therapeutic option for many patients.
Remote Ischemic Conditioning Heusch, Gerd, MD; Bøtker, Hans Erik, MD, PhD; Przyklenk, Karin, PhD ...
Journal of the American College of Cardiology,
01/2015, Volume:
65, Issue:
2
Journal Article
Peer reviewed
Open access
Abstract In remote ischemic conditioning (RIC), brief, reversible episodes of ischemia with reperfusion in one vascular bed, tissue, or organ confer a global protective phenotype and render remote ...tissues and organs resistant to ischemia/reperfusion injury. The peripheral stimulus can be chemical, mechanical, or electrical and involves activation of peripheral sensory nerves. The signal transfer to the heart or other organs is through neuronal and humoral communications. Protection can be transferred, even across species, with plasma-derived dialysate and involves nitric oxide, stromal derived factor-1α, microribonucleic acid-144, but also other, not yet identified factors. Intracardiac signal transduction involves: adenosine, bradykinin, cytokines, and chemokines, which activate specific receptors; intracellular kinases; and mitochondrial function. RIC by repeated brief inflation/deflation of a blood pressure cuff protects against endothelial dysfunction and myocardial injury in percutaneous coronary interventions, coronary artery bypass grafting, and reperfused acute myocardial infarction. RIC is safe and effective, noninvasive, easily feasible, and inexpensive.
Summary Although remote ischemic pre-conditioning (RIPC) reduced infarct size in animal experiments and proof-of-concept clinical trials, recent phase III trials failed to confirm cardioprotection ...during cardiac surgery. Here, we characterized the kinetic properties of humoral factors that are released after RIPC, as well as the signal transduction pathways that were responsible for cardioprotection in an ex vivo model of global ischemia reperfusion injury. Venous blood from 20 healthy volunteers was collected at baseline and 5 min, 30 min, 1 h, 6 h, and daily from 1 to 7 days after RIPC (3 × 5/5 min upper-limb ischemia/reperfusion). Plasma-dialysates (cut-off: 12 to 14 kDa; dilution: 1:20) were infused into Langendorff-perfused mouse hearts subjected to 20/120 min global ischemia/reperfusion. Infarct size and phosphorylation of signal transducer and activator of transcription (STAT)3, STAT5, extracellular-regulated kinase 1/2 and protein kinase B were determined. In a subgroup of plasma-dialysates, an inhibitor of STAT3 (Stattic) was used in mouse hearts. Perfusion with baseline-dialysate resulted in an infarct size of 39% of ventricular mass (interquartile range: 36% to 42%). Perfusion with dialysates obtained 5 min to 6 days after RIPC significantly reduced infarct size by ∼50% and increased STAT3 phosphorylation beyond that with baseline-dialysate. Inhibition of STAT3 abrogated these effects. These results suggest that RIPC induces the release of cardioprotective, dialyzable factor(s) within 5 min, and that circulate for up to 6 days. STAT3 is activated in murine myocardium by RIPC-induced human humoral factors and is causally involved in cardioprotection.
This review summarizes the current literature and the open questions regarding the physiology and pathophysiology of the mechanical effects of heart rate on the vessel wall and the associated ...molecular signaling that may have implications for patient care. Epidemiological evidence shows that resting heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease. As a consequence, increased resting heart rate has emerged as an independent risk factor both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental and clinical data suggest that sustained elevation of heart rate—independent of the underlying trigger—contributes to the pathogenesis of vascular disease. In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis. The underlying mechanisms are only partially understood and appear to involve alterations of mechanic properties such as reduction of vascular compliance. Clinical studies reported a positive correlation between increased resting heart rate and circulating markers of inflammation. In patients with coronary heart disease, increased resting heart rate may influence the clinical course of atherosclerotic disease by facilitation of plaque disruption and progression of coronary atherosclerosis. While a benefit of pharmacological or interventional heart rate reduction on different vascular outcomes was observed in experimental studies, prospective clinical data are limited, and prospective evidence determining whether modulation of heart rate can reduce cardiovascular events in different patient populations is needed.
Objective Remote ischemic preconditioning protects the myocardium from ischemia/reperfusion injury. We recently identified protection by remote ischemic preconditioning to be associated with the ...activation of signal transducer and activator of transcription 5 in left ventricular biopsy specimens of patients undergoing coronary artery bypass grafting during isoflurane anesthesia. Because remote ischemic preconditioning did not protect the heart during propofol anesthesia, we hypothesized that propofol anesthesia interferes with signal transducer and activator of transcription 5 activation. Methods In a randomized, single-blind, placebo-controlled, prospective study, we analyzed an array of established cardioprotective proteins during propofol anesthesia with or without remote ischemic preconditioning in 24 nondiabetic patients with 3-vessel coronary artery disease. Results Remote ischemic preconditioning (n = 12) compared with no remote ischemic preconditioning (n = 12) failed to decrease the area under the troponin I time curve (273 ± 184 ng/mL × 72 hours vs 365 ± 301 ng/mL × 72 hours; P = .374). Although phosphorylation of several protein kinases was increased from baseline to reperfusion, signal transducer and activator of transcription 5 phosphorylation was not increased and was not different between the remote ischemic preconditioning and no remote ischemic preconditioning groups. Conclusions Remote ischemic preconditioning during propofol anesthesia did not evoke either signal transducer and activator of transcription 5 activation or cardioprotection, implying interaction of propofol with cardioprotective signaling upstream of signal transducer and activator of transcription 5.
Abstract Objectives This study sought to analyze health-related quality-of-life (HrQoL) outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) based on data from GARY (German ...Aortic Valve Registry). Background Typically, patients currently referred for and treated by TAVR are elderly with a concomitant variable spectrum of multiple comorbidities, disabilities, and limited life expectancy. Beyond mortality and morbidity, the assessment of HrQoL is of paramount importance not only to guide patient-centered clinical decision-making but also to judge this new treatment modality in this high-risk patient population. Methods In 2011, 3,875 patients undergoing TAVR were included in the GARY registry. HrQoL was prospectively measured using the EuroQol 5 dimensions questionnaire self-complete version on paper at baseline and 1 year. Results Complete follow-up EuroQol 5 dimensions questionnaire evaluation was available for 2,288 patients (transvascular transcatheter aortic valve replacement TAVR-TV: n = 1,626 and transapical TAVR TAVR-TA: n = 662). In-hospital mortality was 5.9% (n = 229) and the 1-year mortality was 23% (n = 893). The baseline visual analog scale score for general health status was 52.6% for TAVR-TV and 55.8% for TAVR-TA and, in parallel to an improvement in New York Heart Association functional class, improved to 59.6% and 58.5% at 1 year, respectively (p < 0.001). Between baseline and 1 year, the number of patients reporting no complaints increased by 7.8% (TAVR-TV) and by 3.5% within the mobility dimension, and by 14.1% (TAVR-TV) and 9.2% within the usual activity dimension, whereas only moderate changes were found for the self-care, pain or discomfort, and anxiety or depression dimensions. In a multiple linear regression analysis several pre- and post-operative factors were predictive for less pronounced HrQoL benefits. Conclusions TAVR treatment led to improvements in HrQoL, especially in terms of mobility and usual activities. The magnitude of improvements was higher in the TAVR-TV group as compared to the TAVR-TA group. However, there was a sizable group of patients who did not derive any HrQoL benefits. Several independent pre- and post-operative factors were identified being predictive for less pronounced HrQoL benefits.
Remote ischemic conditioning (RIC) induces the release of circulating cardioprotective factors and attenuates myocardial ischemia/reperfusion injury. Evidence for such humoral cardioprotective ...factor(s) is derived from transfer with plasma (derivatives) from one individual undergoing RIC to another individual’s heart, even across species. With transfer into an isolated perfused heart, only a single plasma (derivative) sample can be studied with infarct size as endpoint, and therefore the comparison of samples before and after RIC or between RIC and placebo is hampered by the inter-individual variation of infarct sizes in isolated perfused hearts. We therefore developed a preparation of cardiomyocytes from a single mouse heart, where aliquots of the same heart can undergo hypoxia/reoxygenation (H/R) with exposure to buffer, RIC, or placebo samples without or with pharmacological blockade. To validate this approach, we used plasma dialysates taken before and after RIC from patients undergoing coronary bypass grafting who had experienced protection by RIC (troponin release ↓ by 28% vs placebo). The cardiomyocyte bioassay had little variation after H/R with buffer (mean ± standard deviation; 7% ± 2% viable cells) and demonstrated preserved viability after RIC (15% ± 5% vs 6% ± 3% before). For comparison, infarct size in isolated mouse hearts after global ischemia and reperfusion was 22% ± 14% of left ventricular mass after versus 42% ± 14% before RIC. Stattic, an inhibitor of signal transducer and activator of transcription (STAT)3 protein, abrogated protection in the cardiomyocytes. We have thus established a cardiomyocyte bioassay to analyze RIC’s protection which minimizes inter-individual variation and the use of animals.
Summary Remodelling is a response of the myocardium and vasculature to a range of potentially noxious haemodynamic, metabolic, and inflammatory stimuli. Remodelling is initially functional, ...compensatory, and adaptive but, when sustained, progresses to structural changes that become self-perpetuating and pathogenic. Remodelling involves responses not only of the cardiomyocytes, endothelium, and vascular smooth muscle cells, but also of interstitial cells and matrix. In this Review we characterise the remodelling processes in atherosclerosis, vascular and myocardial ischaemia–reperfusion injury, and heart failure, and we draw attention to potential avenues for innovative therapeutic approaches, including conditioning and metabolic strategies.
Summary Background Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft (CABG) surgery. We investigated the safety and ...efficacy of this procedure. Methods Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre, Essen, Germany, between April, 2008, and October, 2012. Patients were prospectively randomised to receive remote ischaemic preconditioning (three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia) or no ischaemic preconditioning (control). The primary endpoint was myocardial injury, as reflected by the geometric mean area under the curve (AUC) for perioperative concentrations of cardiac troponin I (cTnI) in serum in the first 72 h after CABG. Mortality was the main safety endpoint. Analysis was done in intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov , number NCT01406678. Findings 329 patients were enrolled. Baseline characteristics and perioperative data did not differ between groups. cTnI AUC was 266 ng/mL over 72 h (95% CI 237–298) in the remote ischaemic preconditioning group and 321 ng/mL (287–360) in the control group. In the intention-to-treat population, the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 (95% CI 0·70–0·97, p=0·022). cTnI release remained lower in the per-protocol analysis (0·79, 0·66–0·94, p=0·001). All-cause mortality was assessed over 1·54 (SD 1·22) years and was lower with remote ischaemic preconditioning than without (ratio 0·27, 95% CI 0·08–0·98, p=0·046). Interpretation Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery. Funding German Research Foundation.
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