Precondicionamiento isquémico remoto: bases de la protección y resultados clínicos / Remote ischemic preconditioning: Bases and clinical results

El precondicionamiento isquémico remoto es una manera eficaz de disminuir el daño por isquemia y reperfusión en el corazón y otros órganos como cerebro o riñón, en modelos experimentales. Este consiste en realizar entre 3 y 5 ciclos de 5 minutos de isquemia seguidos del mismo tiempo de reperfusión, en un tejido alejado del que se quiere proteger, normalmente una extremidad. Estudios preclínicos en animales indican que la isquemia precondicionante inicia señales nerviosas y humorales en el tejido isquémico remoto, que en el corazón activan mecanismos de protección. La señal nerviosa se origina en fibras sensoriales que a nivel cerebral producen una activación del sistema parasimpático. El nervio vago activa ganglios cardíacos intrínsecos del corazón lo que induce protección. Además, desde el tejido isquémico se liberan a la circulación diferentes mediadores que viajan en forma libre o en vesículas lipídicas (exosomas) que inician vías de señalización protectoras en el corazón. A pesar del éxito del precondicionamiento isquémico remoto en animales de experimentación, su aplicación en seres humanos no ha tenido resultados claros. Esta discrepancia puede deberse a una diversidad de factores tales como la edad, la existencia de otras patologías, uso de fármacos u otros tratamientos que afectan la respuesta de los pacientes. Se requiere un mayor conocimiento de las bases moleculares de este mecanismo de protección para que su aplicación en clínica sea exitosa.

In experimental models, remote ischemic preconditioning effectively decreases ischemia reperfusion injury to the heart and other organs such as the brain or kidney. It consists of 3 to 5 cycles of 5 minutes of ischemia followed by 5 minutes of reperfusion, in a remote tissue, usually a limb. Preclinical studies in animals indicate that preconditioning ischemia initiates neural and humoral signals in the remote ischemic tissue, which activate protective mechanisms in the heart. The nervous signal originates in sensory fibers that activate the parasympathetic system in the brain. The vagus nerve activates the intrinsic cardiac ganglia of the heart, leading to protection from ischemic injury. Furthermore, mediators are released from the ischemic tissue into the circulation that travels freely or in lipid vesicles (exosomes) to the heart where they initiate protective signaling pathways. Despite the success of remote ischemic preconditioning in experimental animals, its application in humans has not produced clear results. This discrepancy may be due to a variety of factors such as age, the existence of other pathologic processes, or the use of drugs or other treatments that affect the patient´s response. An increased knowledge of the molecular bases of this protective mechanism is required for its clinical application to be successful.

Remote Ischemic Conditioning: The Commercial Market: LifeCuff Perspective.

Although remote ischemic conditioning promises significant benefit to patients with a variety of acute and chronic illnesses, development of automated, clinically applicable devices has been slow. At least 3 small companies have launched efforts to develop useful tools intended for sale in European and North American markets. The market challenges and opportunities linked to the development of a cost-effective, reliable, and clinically effective device for the application of remote ischemic conditioning are presented in this article.

[Cardioprotection via the arm? : How a blood pressure cuff decreases infarct sizes]. / Kardioprotektion über den Arm? : Wenn eine Blutdruckmanschette den Herzinfarkt verkleinert.

Cardiovascular diseases and especially myocardial infarctions are responsible for a high morbidity and mortality throughout Europe. An essential aspect of myocardial infarction is ischemia/reperfusion injury which represents the necrosis of myocytes following reperfusion. One possible option to counteract ischemia/reperfusion injury is the much researched process of remote ischemic conditioning (RIC), whereby a certain tissue (e.g. skeletal muscle) is subjected to several cycles of short periods (e.g. 5 min) of ischemia and reperfusion and leads to the protection of another organ (e.g. the heart). Despite substantial efforts to elucidate the underlying mechanisms during the last decades, this phenomenon is not yet completely understood. Clinical studies mainly concentrated on laboratory and radiological parameters, which led to better understanding of RIC; however, large clinical studies evaluating the possible influence on mortality are still lacking. This review article provides an introduction to RIC and summarizes the current understanding of known pathomechanisms and the results of important clinical studies.

Determination of the tensile mechanical properties of the segmented mitral valve annulus.

The mitral valve annulus is a complex and irregular component of the mitral valve apparatus, serving both a structural and sphincteric role. We have sought to determine the mechanical properties of the mitral valve annulus segmentally. Twenty porcine hearts were dissected to isolate the annulus. The annulus was segmented into four sections: anterior, posterior, and left and right commissural sections. Ten of these were tensile tested to failure as control samples. The remaining ten were digested in order to fully isolate the annulus from the myocardium, and subsequently tensile tested to failure. Histological samples of each segment were analysed to determine collagen/annular content. Whole segments of muscular annulus were tensile tested to failure; the stress and strain at failure and location of failure were determined in these larger specimens. Our results demonstrated that the anterior annulus is stiffer than the posterior segment by a factor of approximately 27 at a 2% strain level, and approximately 13 at a 6% strain. There is a trend in the results that identifies that the muscular annulus is stiffest at the right commissural segment, while the posterior segment tends to be the least stiff. The stiffness of the samples can be correlated with the area associated with the dense collagen annulus using histological analysis. Finally, the weakest section of the mitral valve annulus was identified as the intersection of the right commissural segment and the posterior segment.

Effect of pressure-controlled intermittent coronary sinus occlusion (PICSO) on myocardial ischaemia and reperfusion in a closed-chest porcine model.

AIMS: To investigate a pressure-controlled intermittent coronary sinus occlusion (PICSO) system in an ischaemia/reperfusion model. METHODS AND RESULTS: We randomly assigned 18 pigs subjected to 60 minutes ischaemia by left anterior descending (LAD) coronary artery balloon occlusion to PICSO (n=12, groups A and B) or to controls (n=6, group C). PICSO started 10 minutes before (group A), or 10 minutes after (group B) reperfusion and was maintained for 180 minutes. A continuous drop of distal LAD pressure was observed in group C. At 180 minutes of reperfusion, LAD diastolic pressure was significantly lower in group C compared to groups A and B (p=0.02). LAD mean pressure was significantly less than the systemic arterial mean pressure in group C (p=0.02), and the diastolic flow slope was flat, compared to groups A and B (p=0.03). IgG and IgM antibody deposition was significantly higher in ischaemic compared to non-ischaemic tissue in group C (p<0.05). Significantly more haemorrhagic lesions were seen in the ischaemic myocardium of group C, compared to groups A and B (p=0.002). The necrotic area differed non-significantly among groups. CONCLUSIONS: PICSO was safe and effective in improving coronary perfusion pressure and reducing antibody deposition consistent with reduced microvascular obstruction and ischaemia/reperfusion injury.

Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function.

OBJECTIVE: This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. DESIGN: Prospective case-control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. SETTING: University Hospital. PATIENTS: 35 patients with chronic stable coronary artery disease. INTERVENTION: 2-min iCSO. MAIN OUTCOME MEASURES: Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. RESULTS: I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33±1.25 mV versus 1.85±1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r(2)=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05-0.20, whereas in the low and high CFI range the effect of iCSO was absent. CONCLUSIONS: ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place.

Use of a hanging weight system for coronary artery occlusion in mice.

Murine studies of acute injury are an area of intense investigation, as knockout mice for different genes are becoming increasingly available. Cardioprotection by ischemic preconditioning (IP) remains an area of intense investigation. To further elucidate its molecular basis, the use of knockout mouse studies is particularly important. Despite the fact that previous studies have already successfully performed cardiac ischemia and reperfusion in mice, this model is technically very challenging. Particularly, visual identification of the coronary artery, placement of the suture around the vessel and coronary occlusion by tying off the vessel with a supported knot is technically difficult. In addition, re-opening the knot for intermittent reperfusion of the coronary artery during IP without causing surgical trauma adds additional challenge. Moreover, if the knot is not tied down strong enough, inadvertent reperfusion due to imperfect occlusion of the coronary may affect the results. In fact, this can easily occur due to the movement of the beating heart. Based on potential problems associated with using a knotted coronary occlusion system, we adopted a previously published model of chronic cardiomyopathy based on a hanging weight system for intermittent coronary artery occlusion during IP. In fact, coronary artery occlusion can thus be achieved without having to occlude the coronary by a knot. Moreover, reperfusion of the vessel can be easily achieved by supporting the hanging weights which are in a remote localization from cardiac tissues. We tested this system systematically, including variation of ischemia and reperfusion times, preconditioning regiments, body temperature and genetic backgrounds. In addition to infarct staining, we tested cardiac troponin I (cTnI) as a marker of myocardial infarction in this model. In fact, plasma levels of cTnI correlated with infarct sizes (R2=0.8). Finally, we could show in several studies that this technique yields highly reproducible infarct sizes during murine IP and myocardial infarction. Therefore, this technique may be helpful for researchers who pursue molecular mechanisms involved in cardioprotection by IP using a genetic approach in mice with targeted gene deletion. Further studies on cardiac IP using transgenic mice may consider this technique.

The in-situ pig heart with regional ischemia/reperfusion - ready for translation.

The pig heart in situ with regional myocardial ischemia and reperfusion is of unique translational value. Cardiac size, heart rate and blood pressure are similar to those in humans. The temporal and spatial development of myocardial infarction resembles that seen in humans. Technically, the pig heart permits precise control of coronary blood flow during ischemia and reperfusion, includes an intra-individual remote control zone for comparison, and permits the sequential sampling of microdialysates and biopsies for further biochemical, molecular and morphological analyses. Conceptually, all cardioprotective phenomena, including hibernation, ischemic preconditioning, ischemic postconditioning, and remote conditioning, have been demonstrated in pig hearts. The cardioprotective signalling is in part similar, but in part also different from that in rodent hearts.

Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction: a pilot study.

The objective of this study was to determine whether acutely ischemic myocardium may be conditioned during percutaneous coronary intervention for acute myocardial infarction. Ischemic preconditioning is a powerful cardioprotective mechanism that limits infarct size in animal investigations and ischemic sequelae during percutaneous coronary intervention in man. However, the conditioning stimulus in all these studies has been applied prior to the defining episode of ischemia. Seventeen patients undergoing percutaneous coronary intervention for acute myocardial infarction were randomly assigned to a standard ischemic preconditioning protocol (n = 10) or a usual-care control group (n =7). ST segment shift response and Doppler-derived distal coronary velocity data were compared. Despite similar degrees of baseline ST segment elevation, the magnitude of final ST segment elevation in the conditioning group was less than that in controls at the protocol conclusion (conditioning, 1.60 +/- 0.8 mV; control, 4.0 +/- 0.5 mV; P < 0.001). The rate of ST segment resolution was greater in the conditioning group (conditioning, 0.28 +/- 0.1 mV/min; control, 0.12 +/- 0.1 mV/min; P = 0.02). Distal coronary velocimetry indicated significant improvement in coronary flow velocity reserve in the conditioning group at the protocol conclusion (conditioning, 1.8 +/- 0.2; control, 1.4 +/- 0.1; P < 0.008). Brief periods of occlusion and reperfusion during percutaneous intervention for acute myocardial infarction mitigate the extent of ischemic injury and improve distal myocardial perfusion. Such ischemic conditioning represents a potentially useful adjunct to strategies for enhancing reperfusion during acute myocardial infarction.