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.

Ultrasound biomicroscopy validation of a murine model of cardiac hypertrophic preconditioning: comparison with a hemodynamic assessment.

In mice, myocardial hypertrophic preconditioning (HP), which is produced by the removal of short-term transverse aortic constriction (TAC), was recently reported to render the heart resistant to hypertrophic responses induced by subsequent reconstriction (Re-TAC). However, there is no efficient noninvasive method for ensuring that the repeated aortic manipulations were successfully performed. We previously demonstrated that ultrasound biomicroscopy (UBM) is a noninvasive and effective approach for predicting TAC success. Here, we investigated the value of UBM for serial predictions of load conditions in establishing a murine HP model. C57BL/6J mice were subjected to a sham operation, TAC, or Re-TAC, and the peak flow velocity at the aortic banding site (PVb) was measured by UBM. Left ventricular end-systolic pressure (LVESP) was examined by micromanometric catheterization. The PVb was positively associated with LVESP (R2 = 0.8204, P < 0.001, for TAC at 3 days and R2 = 0.7746, P < 0.001, for Re-TAC at 4 wk). PVb and LVESP values were markedly elevated after aortic banding, became attenuated to the sham-operated level after debanding, and increased after aortic rebanding. The cardiac hypertrophic responses were examined by UBM, histology, RT-PCR, and Western blot analysis. Four weeks after the last operation, with PVb ≥ 3.5 m/s as an indicator of successful aortic constriction, Re-TAC mice showed less cardiac hypertrophy, fetal gene expression, and ERK1/2 activation than TAC mice. Therefore, we successfully established a UBM protocol for the serial assessment of aortic flow and the prediction of LVESP during repeated aortic manipulations in mice, which might be useful for noninvasive evaluations of the murine HP model.NEW & NOTEWORTHY We successfully developed an ultrasound biomicroscopy protocol for the serial assessment of aortic bandings and the relevant left ventricular pressure in a murine model of cardiac hypertrophic preconditioning. The protocol may be of great importance in the successful establishment of the hypertrophic preconditioning model for further mechanistic and pharmacological studies.

In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed-chest porcine model of reperfused acute myocardial infarction: importance of microvasculature.

BACKGROUND: Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI. METHODS AND RESULTS: Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 × 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 × 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 × 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO. CONCLUSION: We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis.

Protective effects of hyperbaric oxygen therapy (HBO2) in cardiac care--A proposal to conduct a study into the effects of hyperbaric pre-conditioning in elective coronary artery bypass graft surgery (CABG).

We review and report on accumulated data showing the benefits offered by hyperbaric oxygen (HBO2) therapy as an adjunct in the treatment of coronary artery bypass graft (CABG) patients. It has been shown that ischemia-reperfusion injury is deleterious to the myocardium, causing left ventricular dysfunction, structural damage to the myocytes and endothelial cells, myocardial stunning, reperfusion arrhythmias and potentially irreversible injury. There is a substantial body of evidence pointing to the role of HBO2 in mitigating the harmful effects of ischemia-reperfusion injury. Specifically, we review evidence from a number of studies which clearly point to both clinical and cost benefits HBO2 offers when used to precondition non-emergent patients having on-pump coronary arterial bypass graft surgery. Study data show that adding adjunctive HBO2 into the plan of care leads to improved myocardial function, reduces length of stay in the ICU, and limits post-surgical complications. Further, it has only minimal impact on the presurgical preparation, i.e., time must be allowed for the hyperbaric treatment(s), and no role in the surgery or post-surgical care of the patient. The studies pointing to clinical and cost benefit of preconditioning have been conducted outside the United States. Given the pressure on costs in all areas of health care, it seems that a therapeutic approach, which has been shown to be of benefit in both animal and human trials over the course of many years, should attract funding for a properly structured study designed to test whether significant and simultaneous improvements in clinical outcomes and cost reductions can be achieved within the framework of a U.S. healthcare facility.

The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs.

RATIONALE: Despite 4 decades of intense effort and substantial financial investment, the cardioprotection field has failed to deliver a single drug that effectively reduces myocardial infarct size in patients. A major reason is insufficient rigor and reproducibility in preclinical studies. OBJECTIVE: To develop a multicenter, randomized, controlled, clinical trial-like infrastructure to conduct rigorous and reproducible preclinical evaluation of cardioprotective therapies. METHODS AND RESULTS: With support from the National Heart, Lung, and Blood Institute, we established the Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR), based on the principles of randomization, investigator blinding, a priori sample size determination and exclusion criteria, appropriate statistical analyses, and assessment of reproducibility. To validate CAESAR, we tested the ability of ischemic preconditioning to reduce infarct size in 3 species (at 2 sites/species): mice (n=22-25 per group), rabbits (n=11-12 per group), and pigs (n=13 per group). During this validation phase, (1) we established protocols that gave similar results between centers and confirmed that ischemic preconditioning significantly reduced infarct size in all species and (2) we successfully established a multicenter structure to support CAESAR's operations, including 2 surgical centers for each species, a Pathology Core (to assess infarct size), a Biomarker Core (to measure plasma cardiac troponin levels), and a Data Coordinating Center-all with the oversight of an external Protocol Review and Monitoring Committee. CONCLUSIONS: CAESAR is operational, generates reproducible results, can detect cardioprotection, and provides a mechanism for assessing potential infarct-sparing therapies with a level of rigor analogous to multicenter, randomized, controlled clinical trials. This is a revolutionary new approach to cardioprotection. Importantly, we provide state-of-the-art, detailed protocols ("CAESAR protocols") for measuring infarct size in mice, rabbits, and pigs in a manner that is rigorous, accurate, and reproducible.

Ischaemic preconditioning reduces myocardial calcium overload in coronary-occluded pig hearts shown by continuous in vivo assessment using microdialysis.

During ischaemia, ATP depletion leads to insufficient fuelling for Na(+) /K(+) ATPase, decreased electrochemical potential and increased influx of calcium ions. This study demonstrated a means to assess the effects of ischaemic preconditioning (IP) on the free intracellular Ca(2+) pool during prolonged ischaemia. In a porcine myocardial ischaemia model, microdialysis (MD) was used for sampling of metabolic and injury markers in IP and non-IP (control) groups. (45) Ca(2+) was delivered in microperfusate locally to ischaemic myocardium, with distribution and uptake assessed by (45) Ca(2+) recovery in microdialysate. Cardiomyocytes in vitro were exposed to a Ca(2+) ionophore and tested for (45) Ca(2+) uptake. An accentuated myocardial calcium ion influx (observed as an increased microdialysate (45) Ca(2+) recovery in the extracellular milieu) was noted in control pigs compared with IP pigs during ischaemia. Suspended cardiomyocytes preincubated with a Ca(2+) ionophore to increase the intracellular calcium ion pool and subsequently incubated with (45) Ca(2+) , displayed lower (45) Ca(2+) uptake in cells compared with control cells not exposed to the ionophore, corroborating the idea of a strong relationship between degree of intracellular calcium overload and microdialysate (45) Ca(2+) recovery. The ischaemic insult was differentially verified by metabolic and injury markers. We introduce an in vivo method for serial assessment of myocardial calcium overload during ischaemia, using a MD technique and (45) Ca(2+) inclusion. IP leads to relatively less calcium overload as assessed by this new method, and we interpret this to mean that reduction in calcium overload is an important part of the IP protective effect.

In vivo fluorometric assessment of cyclosporine on mitochondrial function during myocardial ischemia and reperfusion.

BACKGROUND: Cyclosporine A (CsA) limits myocardial reperfusion injury and preserves mitochondrial integrity, but its influence on mitochondrial function has not been described in vivo. Auto-fluorescence of mitochondrial nicotinamide adenine dinucleotide and flavin adenine dinucleotide correlate with mitochondrial dysfunction. We hypothesized that CsA limits mitochondrial dysfunction and that fluorometry can quantify this influence. METHODS: Seventeen rabbits were studied: untreated (UnT, n = 7), CsA preinfarction (CsAp, n = 6), and CsA on reperfusion (CsAr, n = 4). Animals underwent 30 minutes of myocardial ischemia and 3 hours reperfusion. Infarct size was determined by staining. Nicotinamide adenine dinucleotide and flavin adenine dinucleotide fluorescence was continually measured in the risk area. The redox ratio was calculated [flavin adenine dinucleotide(f)/(flavin adenine dinucleotide(f) + nicotinamide adenine dinucleotide(f))]. Electron microscopy evaluated mitochondria morphology. RESULTS: The infarct size by group was 39.1% +/- 1.7% in CsAp, 39.1% +/- 1.7% in CsAr, and 53.4% +/- 1.9% in UnT (p < 0.001). During ischemia, the CsAp group demonstrated less hypoxic reduction, with the redox ratio decreasing to 75.6% +/- 4.1% of baseline. The UnT and CsAr groups deceased to 67.1% +/- 4.0% and 67.2% +/- 3.6%, respectively (p < 0.005). During reperfusion the UnT group redox ratio increased to 1.59 +/- 0.04 times baseline. This increase was blunted in the CsAp (1.17 +/- 0.04, p = 0.026) and CsAr (1.35 +/- 0.02, p = 0.056) groups. Electron microscopy revealed reduced mitochondrial disruption in CsAp (19.7% +/- 7.6%) and CsAr (18.1% +/- 7.1%) rabbits compared with UnT (53.3% +/- 12.5%). CONCLUSIONS: Fluorometric spectroscopy can be used in vivo to quantitatively assess the time course of CsA's influence on the mitochondrial dysfunction associated with myocardial ischemia and reperfusion.

Multiparameter fiber optic sensor for the assessment of intramyocardial perfusion.

OBJECTIVES: The objective of this study was to characterize a multiparameter fiber optic sensor for detection of changes in intramyocardial perfusion and to demonstrate a method of determining critical values for pH, PCO2, and PO2 to indicate onset of anaerobic metabolism. METHODS: Six swine underwent a 20-minute occlusion of the left anterior descending coronary artery (LAD). Myocardial pH, PCO2, and PO2 were measured continuously in the LAD and left circumflex coronary artery (CFX) territories. Critical values for each parameter were calculated from these data. RESULTS: During occlusion LAD myocardial pH declined from 7.36 +/- 0.04 to 6.85 +/- 0.04; PCO2 rose from 57.0 +/- 2.9 to 154.0 +/- 18.0 torr, PO2 fell from 78 +/- 20 to 6 +/- 5 torr. No myocardial pH or PCO2 changes were observed in the CFX region, however, CFX PO2 was affected in some animals during LAD occlusion and release. Methods for determining the ischemic threshold from these sensor data are presented. CONCLUSIONS: Multiparameter fiber optic sensors reliably respond to coronary occlusion and thus have the potential to help guide myocardial protection strategies for both on- and off-pump cardiac surgery.

Intermittent aortic cross-clamping for coronary artery bypass grafting: a review of a safe, fast, simple, and successful technique.

Since the very beginning of coronary artery bypass grafting, the search for optimal myocardial protection has fascinated both clinicians and basic researchers. This retrospective review of a large patient cohort aims to display the advantages of one of the protective procedures, namely simple, intermittent aortic cross-clamping (IAC). Thus, this review aims to significantly contribute to daily bypass surgery. This review reports on coronary patients who were all operated on in international centers using IAC such that this review presents the state of the art on IAC. In addition, this review reports on the usage of IAC for more than 2 decades in the clinic of Dr. Bircks, Duesseldorf (DE) and the clinics of his former students. A meta-analysis of published data of international centers summarizes 7 837 operated patients with a total mortality of 123 (=1.6%). This excellent outcome compares well to the results of the Bircks'-related centers, where between 1978 and 2001, a total of 41 573 patients were revascularized with the help of IAC according to the original protocol. The total mortality was 778 (1.9%), with the lowest mortality rate (1.2%) in the largest center (Bad Oeynhausen, DE). According to the presented experience, IAC for coronary revascularization proves to be a highly effective method for myocardial protection; it has convincingly proven to be simple, safe and cost-efficient.

Norepinephrine-induced delayed cardioprotection against stunning is at the expense of a higher postischemic arrhythmia rate.

OBJECTIVE: alpha(1)-adrenoceptor activation confers myocardial protection from ischemic injury. We tested whether norepinephrine mediates delayed cardioprotection against stunning and whether this alters postischemic arrhythmias. METHODS: New Zealand White rabbits were assigned to three groups: Control-group (n=7): no drugs. Norepinephrine-group (n=7): 75 microg norepinephrine/kg bodyweight (bw). Norepinephrine/prazosin-group (n=7):75 microg norepinephrine and 15 microg prazosin/kg bw. After 24 h, hearts were excised, perfused with buffer and subjected to 20 min of ischemia followed by 120 min of reperfusion. RESULTS: (a) Developed pressures (dP) (P(syst)-P(diast)) at the end of reperfusion: C: 51.2+/-5.0%, NE: 71.7+/-5.1% (p<0.05 vs. C), NEP: 50.7+/-5.0%. (b) Ventricular extra beats (vebs) were detected throughout the experiments. C: 0.41+/-0.15 vebs/min, NE: 1.06+/-0.18 vebs/min (p<0.05 vs. C), NEP: 1.17+/-0.3 vebs/min. CONCLUSION: Norepinephrine confers delayed preconditioning against myocardial stunning via an alpha(1)-adrenoceptor mediated pathway. Norepinephrine-mediated preconditioning involves a beneficial effect towards stunning, but at the expense of a higher rate of postischemic ventricular arrhythmia.

Pre-conditioning activates adenosine utilization in a cost-effective way during myocardial ischaemia.

During pre-conditioning the interstitial concentration of adenosine, in contrast to lactate, presents a die-away curve-pattern for every successive episode of ischaemia. This die-away pattern might not necessarily be attributed to diminished adenosine production. The present study was undertaken to investigate whether pre-conditioning alters the metabolic turnover of adenosine as observed by the lactate production during ischaemia. Interstitial levels of metabolites in pre-conditioned (n=21) and non-preconditioned (n=21) porcine hearts were monitored with microdialysis probes inserted in both ischaemic and non-ischaemic tissue in an open chest heart model. Three subgroups perturbated with either plain microdialysis buffer (control), buffer containing adenosine (375 microM), or buffer containing deoxyadenosine (375 microM) were studied. All animals were subjected to 90 min of equilibrium microdialysis before 40 min of regional myocardial ischaemia and 120 min of reperfusion. Pre-conditioning consisted of four repetitive episodes of 10 min of ischaemia and 20 min of reperfusion. Significantly higher levels of inosine and lactate were found in the ischaemic tissue of the pre-conditioned subgroup receiving adenosine (P < 0.05) compared with the other two subgroups receiving deoxyadenosine and plain buffer, respectively. This difference was only valid for pre-conditioned ischaemic myocardium, and hence equal amounts of inosine and lactate were produced in the non-preconditioned ischaemic myocardium regardless of the presence of adenosine or deoxyadenosine. In the non-ischaemic myocardium baseline levels of metabolites were measured in all subgroups. Pre-conditioning favoured degradation of exogenous adenosine to inosine successively ending up in enhanced lactate production. This was probably because of the involvement of the hexose monophosphate pathway in the pre-conditioned ischaemic myocardium. This route may therefore be supplementary in energy metabolism as a metabolic flow can be started by adenosine ending up in lactate without initial adenosine 5'-triphosphate (ATP) investment. Utilization of adenosine in this way may also explain the successive die-away pattern of adenosine seen in consecutive pre-conditioning cycles.

Effects of repetitive brief ischemia on contractile efficiency and oxygen cost of contractility in dog heart.

It is unclear whether preceding repetitive brief ischemia causes any improvement in the energy efficiency of intracellular calcium cycling or crossbridge cycling that may lead to cardioprotection after subsequent sustained ischemia/reperfusion, a phenomenon called ischemic preconditioning. To address this issue, left ventricular (LV) contractility (E(max)) and the relation between myocardial oxygen consumption (VO(2)) and pressure-volume area (PVA, a measure of LV total mechanical energy) were assessed before (Control) and 20 min (Rep-20) and 60 min (Rep-60) after repetitive brief ischemia in 11 isolated, blood-perfused dog hearts. At Rep-20, E(max) and PVA-independent VO(2) (nonmechanical energy expenditure) decreased by 23.0 +/- 19.5 and 13.9 +/- 18.0%, respectively (both p < 0.05). However, at Rep-60, both E(max) and PVA-independent VO(2) recovered to their respective control levels. The oxygen cost of contractility (the slope of the PVA-independent VO(2)-E(max) relation during CaCl(2) loading) remained constant (Control 0.0019 +/- 0.0009 vs. Rep-60 0.0018 +/- 0.0013 ml O(2) x ml x mmHg(-1) x beat(-1) x 100 g(-2), ns), suggesting unchanged efficiency in Ca(2+) cycling. Also, the contractile efficiency (the reciprocal of the slope of the VO(2)-PVA relation, reflecting the efficiency of crossbridge cycling) was the same between the Control and Rep-60 (53.7 +/- 16.7 vs. 55.4 +/- 14.4%, ns). Basal metabolism VO(2) during KCl arrest was also similar to that in the normal heart. Nonmechanical energy expenditure was reduced in proportion to the decrease in LV contractility after repetitive brief ischemia, while both the contractile efficiency and oxygen cost of contractility remained constant. These results indicate that the heart, after repetitive brief ischemia but before sustained ischemia, has normal efficiencies of crossbridge cycling and Ca(2+) cycling despite the transiently reduced contractility.