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Gerd Heusch - One of the best experts on this subject based on the ideXlab platform.
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the Coronary Circulation in acute myocardial ischaemia reperfusion injury a target for cardioprotection
Cardiovascular Research, 2019Co-Authors: Derek J Hausenloy, William M Chilian, Filippo Crea, Sean M Davidson, Peter Ferdinandy, David Garciadorado, Niels Van Royen, Rainer Schulz, Gerd HeuschAbstract:The Coronary Circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes Coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the Coronary Circulation, including microembolization of debris and release of soluble factors from the culprit lesion, impairment of endothelial integrity with subsequently increased permeability and oedema formation, platelet activation and leucocyte adherence, erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with eventual no-reflow, microvascular obstruction (MVO), and intramyocardial haemorrhage (IMH). Therefore, the Coronary Circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and carries, independently from infarct size, an unfavourable prognosis. MVO and IMH can be diagnosed by modern imaging technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the Coronary Circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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the Coronary Circulation as a target of cardioprotection
Circulation Research, 2016Co-Authors: Gerd HeuschAbstract:The atherosclerotic Coronary vasculature is not only the culprit but also a victim of myocardial ischemia/reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local and remote ischemic pre- and postconditioning not only reduce infarct size but also these manifestations of Coronary vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide, metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused Coronary Circulation is available.
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the Coronary Circulation in cardioprotection more than just one confounder
Cardiovascular Research, 2012Co-Authors: Gerd Heusch, Rainer Schulz, Petra Kleinbongard, Andreas Skyschally, Bodo Levkau, Raimund ErbelAbstract:Cardioprotection, i.e. the reduction in infarct size by pre-, post-, or remote conditioning, has originally been characterized in young and healthy experimental animals. Over the last two decades many signalling steps of cardioprotection have been identified, again in young and healthy animals. Although proof-of-concept studies unequivocally demonstrated the recruitment of all forms of cardioprotection in humans, the translation of cardioprotection to clinical routine has been poor. The apparent lack of translation has been attributed to poor design of clinical trials, but also to the neglect of confounders, such as age, sex, comorbidities, and comedications, in experimental studies. The present opinionated review focuses on the Coronary Circulation as a major determinant of cardioprotection. Coronary occlusion and the restoration of Coronary blood flow are the causes of myocardial ischaemia and reperfusion injury from which protection is sought. On the other hand, brief cycles of Coronary occlusion and reperfusion are also the stimulus for protection from myocardial ischaemia/reperfusion injury. The recruitment of collateral blood flow also contributes to protection from infarction. Finally, the Coronary microCirculation is also a target of both injury by myocardial ischaemia/reperfusion and protection from it. Different manifestations of Coronary artery disease, such as Coronary stenosis or Coronary microembolization, impact on both injury and protection.
John E Mayer - One of the best experts on this subject based on the ideXlab platform.
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natural history of pulmonary atresia with intact ventricular septum and right ventricle dependent Coronary Circulation managed by the single ventricle approach
The Annals of Thoracic Surgery, 2006Co-Authors: Kristine J Guleserian, Laurie B Armsby, Ravi R Thiagarajan, Pedro J Del Nido, John E MayerAbstract:Background Long-term outcome of patients with pulmonary valvar atresia and intact ventricular septum with right-ventricle–dependent Coronary Circulation (PA/IVS-RVDCC) managed by staged palliation directed toward Fontan Circulation is unknown, but should serve as a basis for comparison with management protocols that include initial systemic-to-pulmonary artery shunting followed by listing for cardiac transplantation. Methods Retrospective review of patients admitted to our institution with the diagnosis of PA/IVS-RVDCC from 1989 to 2004. All angiographic imaging studies, operative reports, and follow-up information were reviewed. Right-ventricle–dependent Coronary Circulation was defined as situations in which ventriculoCoronary fistulae with proximal Coronary stenosis or atresia were present, putting significant left ventricle myocardium at risk for ischemia with right ventricle decompression. Results Thirty-two patients were identified with PA/IVS-RVDCC. All underwent initial palliation with modified Blalock-Taussig shunt (BTS). Median tricuspid valve z-score was -3.62 (-2.42 to -5.15), and all had moderate (n = 13) or severe (n = 19) right ventricular hypoplasia. Median follow-up was 5.1 years (9 months to 14.8 years). Overall mortality was 18.8% (6 of 32), with all deaths occurring within 3 months of BTS. AortoCoronary atresia was associated with 100% mortality (3 of 3). Of the survivors (n = 26), 19 have undergone Fontan operation whereas 7, having undergone bidirectional Glenn shunt, currently await Fontan. Actuarial survival by the Kaplan-Meier method for all patients was 81.3% at 5, 10, and 15 years, whereas mean survival was 12.1 years (95% confidence interval: 10.04 to 14.05). No late mortality occurred among those surviving beyond 3 months of age. Conclusions In patients with PA/IVS-RVDCC, early mortality appears related to Coronary ischemia at the time of BTS. Single-ventricle palliation yields excellent long-term survival and should be the preferred management strategy for these patients. Those with aortoCoronary atresia have a particularly poor prognosis and should undergo cardiac transplantation.
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outcome in infants with pulmonary atresia intact ventricular septum and right ventricle dependent Coronary Circulation
American Journal of Cardiology, 2000Co-Authors: Andrew J Powell, John E Mayer, P Lang, James E LockAbstract:Management of all patients with pulmonary atresia, intact ventricular septum, and right ventricle-dependent Coronary Circulation (n = 12) with staged surgery directed toward a Fontan palliation resulted in an 83% 5-year actuarial survival. Both deaths in the study were presumably related to Coronary ischemia and occurred in the first 4 months of life.
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improved results with selective management in pulmonary atresia with intact ventricular septum
The Journal of Thoracic and Cardiovascular Surgery, 1999Co-Authors: Marjan Jahangiri, John E Mayer, Pedro J Del Nido, David Zurakowski, David P Bichell, Richard A JonasAbstract:Abstract Objective: Late outcome of neonatal pulmonary atresia with intact ventricular septum remains poor in most reported series. We have followed a selective approach toward either single ventricle repair versus complete or partial biventricular repair based on the presence of right ventricle–dependent Coronary Circulation and growth of the right ventricle. Methods: A retrospective chart review was conducted of 47 patients who underwent surgery between January 1991 and September 1998. Results: Sixteen (34%) patients had a right ventricle–dependent Coronary Circulation, with a tricuspid valve Z-score of –3.0 ± 0.66 versus –2.0 ± 0.95 ( P = .002) for those without a right ventricle–dependent Coronary Circulation. A systemic–pulmonary artery shunt only was performed in all patients with a right ventricle–dependent Coronary Circulation, with 1 death. Fourteen of 16 patients with a right ventricle–dependent Coronary Circulation underwent a bidirectional Glenn shunt at a median of 9 months after their first operation, 9 of whom have had a Fontan procedure (no deaths). In the 31 (66%) patients without a right ventricle–dependent Coronary Circulation, 6 patients underwent only a systemic–pulmonary artery shunt, 23 had a shunt and right ventricular decompression, and 2 had only a transannular patch. In this group, 10 patients received a 2-ventricle repair, 6 a 1.5-ventricle repair, and 8 patients had a Fontan procedure. There was 1 early death and the overall survival was 98% at 1 year, 5 years, and 7 years. Conclusions: If patients are stratified well, excellent survival can be achieved in the treatment of pulmonary atresia with intact ventricular septum. This result may be at the price of achieving a 1-ventricle as opposed to a 2-ventricle repair. (J Thorac Cardiovasc Surg 1999;118:1046-55)
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diagnosis and management of right ventricle dependent Coronary Circulation in pulmonary atresia with intact ventricular septum
Circulation, 1992Co-Authors: Therese M Giglia, John E Mayer, Valerie S Mandell, A R Connor, James E LockAbstract:BACKGROUNDCoronary artery anomalies including 1) right ventricle (RV)-to-Coronary artery fistulas, 2) Coronary artery stenoses, and 3) Coronary occlusions occur in patients with pulmonary atresia with intact ventricular septum (PA-IVS). In some, a large part of the Coronary blood supply may depend on the RV. This RV-dependent Coronary Circulation may determine survival after right ventricular decompression (RVD): RVD may cause RV "steal" in the presence of fistulas alone and ischemia, Coronary isolation, or myocardial infarction in the presence of Coronary stenoses.METHODS AND RESULTSEighty-two patients with PA-IVS who presented between January 1979 and January 1990 were reviewed; 26 (32%) had RV-to-Coronary artery fistulas. Of these 26, 23 had adequate preoperative Coronary angiograms for analysis. RVD was achieved in 16. Seven of 16 had fistulas only; each survived RVD. Six of 16 had stenosis of a single Coronary artery [left anterior descending Coronary artery (LAD), four; right Coronary artery (RCA), ...
James E Lock - One of the best experts on this subject based on the ideXlab platform.
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outcome in infants with pulmonary atresia intact ventricular septum and right ventricle dependent Coronary Circulation
American Journal of Cardiology, 2000Co-Authors: Andrew J Powell, John E Mayer, P Lang, James E LockAbstract:Management of all patients with pulmonary atresia, intact ventricular septum, and right ventricle-dependent Coronary Circulation (n = 12) with staged surgery directed toward a Fontan palliation resulted in an 83% 5-year actuarial survival. Both deaths in the study were presumably related to Coronary ischemia and occurred in the first 4 months of life.
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diagnosis and management of right ventricle dependent Coronary Circulation in pulmonary atresia with intact ventricular septum
Circulation, 1992Co-Authors: Therese M Giglia, John E Mayer, Valerie S Mandell, A R Connor, James E LockAbstract:BACKGROUNDCoronary artery anomalies including 1) right ventricle (RV)-to-Coronary artery fistulas, 2) Coronary artery stenoses, and 3) Coronary occlusions occur in patients with pulmonary atresia with intact ventricular septum (PA-IVS). In some, a large part of the Coronary blood supply may depend on the RV. This RV-dependent Coronary Circulation may determine survival after right ventricular decompression (RVD): RVD may cause RV "steal" in the presence of fistulas alone and ischemia, Coronary isolation, or myocardial infarction in the presence of Coronary stenoses.METHODS AND RESULTSEighty-two patients with PA-IVS who presented between January 1979 and January 1990 were reviewed; 26 (32%) had RV-to-Coronary artery fistulas. Of these 26, 23 had adequate preoperative Coronary angiograms for analysis. RVD was achieved in 16. Seven of 16 had fistulas only; each survived RVD. Six of 16 had stenosis of a single Coronary artery [left anterior descending Coronary artery (LAD), four; right Coronary artery (RCA), ...
William H. Simmons - One of the best experts on this subject based on the ideXlab platform.
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cardioprotective effects of the aminopeptidase p inhibitor apstatin studies on ischemia reperfusion injury in the isolated rat heart
Journal of Cardiovascular Pharmacology, 1999Co-Authors: Çağatay Erşahin, David E Euler, William H. SimmonsAbstract:Summary:Aminopeptidase P and angiotensin-converting enzyme (ACE) are responsible for the metabolism of exogenously administered bradykinin in the Coronary Circulation of the rat. It has been shown that ACE inhibitors decrease cytosolic enzyme release from the ischemic rat heart and reduce reperfusio
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inhibition of both aminopeptidase p and angiotensin converting enzyme prevents bradykinin degradation in the rat Coronary Circulation
Journal of Cardiovascular Pharmacology, 1997Co-Authors: Çağatay Erşahin, William H. SimmonsAbstract:Bradykinin (Bk), which is produced locally in the heart, exhibits potent cardioprotective effects. However, these effects appear to be limited by rapid degradation of the peptide. To determine the mechanism of Bk metabolism in the Coronary Circulation, [ 3 H]Bk was perfused through the isolated rat heart via the aorta in the presence and absence of specific peptidase inhibitors. The radiolabeled metabolites were collected from the pulmonary artery and then separated, identified, and quantified by reversed-phase high-performance liquid chromatography (HPLC) by using a radioactive flow detector. In the absence of inhibitors, only 45 ± 2% of the radioactivity eluted from the Coronary Circulation as intact [ 3 H]Bk. The chromatograms suggested that Bk was being hydrolyzed at the Arg 1 -Pro 2 bond by aminopeptidase P and at the Pro 7 -Phe 8 bond by angiotensin-converting enzyme. When the aminopeptidase P inhibitor, apstatin (200 μM), was coperfused with [ 3 H]Bk, cleavage at the Arg 1 -Pro 2 bond was blocked and the amount of intact [ 3 H]Bk in the perfusate increased to 57 ± 5% (p < 0.05 vs. control). Coperfusion with the angiotensin-converting enzyme inhibitor, ramiprilat (0.5 μM), alone blocked cleavage at the Pro 7 -Phe 8 bond and increased intact [ 3 H]Bk to 75 ± 3% (p < 0.001 vs. control). When both apstatin and ramiprilat were present, almost all of the radioactivity (96 ± 1%) eluted as intact [ 3 H]Bk (p < 0.01 vs. ramiprilat alone). The results indicate that the degradation of Bk in the rat Coronary Circulation can be fully accounted for by aminopeptidase P ( 30%) and angiotensin-converting enzyme (70%).
Henry Gewirtz - One of the best experts on this subject based on the ideXlab platform.
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Coronary Circulation pressure flow parameters for assessment of ischemic heart disease
Journal of Nuclear Cardiology, 2019Co-Authors: Henry GewirtzAbstract:Both invasive and non-invasive parameters have been reported for assessment of the physiological status of the Coronary Circulation. Fractional flow reserve and Coronary (or myocardial) flow reserve may be obtained by invasive or non-invasive means. These metrics of Coronary stenosis severity have achieved wide clinical acceptance for guiding revascularization decisions and risk stratification. Other indices are obtained invasively (e.g., instantaneous wave-free ratio, iFR; hyperemic stenosis resistance) or non-invasively (e.g., PET absolute myocardial blood flow (mL/min/g)) and have been used for the same purposes. Both iFR, and whole-cycle distal Coronary to aortic mean pressure (Pd/Pa) are measured under basal condition and used for assessment of hemodynamic stenosis severity as is index of basal stenosis resistance (BSR). These metrics typically are dichotomized at an empirically derived cut point into “normal” and “abnormal” categories for purposes of clinical decision making and data analysis. Once dichotomized the indices do not always point in the same direction and so confusion may arise. This review, therefore, will present basic principles relevant to understanding commonly employed metrics of the physiological status of the Coronary Circulation, potential strengths and weaknesses, and hopefully an improved appreciation of the clinical information provided by each.
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From Physiology of the Coronary Circulation to Myocardial Perfusion Imaging
Current Cardiovascular Imaging Reports, 2014Co-Authors: Henry GewirtzAbstract:The present paper reviews important recent publications concerning the application of principles of Coronary physiology to quantitative PET myocardial perfusion imaging. Invasive measurements as well as Coronary computed tomography angiography are also considered. The review focuses on physiological concepts relevant to the understanding of the effects of Coronary atherosclerosis on myocardial blood flow (MBF) responses to stress. It also highlights the increasing shift from an anatomical paradigm of stenosis severity assessment to a physiological one, emphasizing the importance of absolute measurements of MBF. Key concepts and supporting literature reviewed in the present paper include quantitative PET measurements of absolute rest and stress MBF, the use of stress MBF alone for physiological assessment of stenosis functional severity, the utility of ratios such as fractional flow reserve (FFR) and Coronary flow reserve (CFR) in assessing stenosis severity, and most importantly, the absolute level of MBF required to sustain vigorous physical exercise (9–10 metabolic equivalents (METs)) in healthy adults.
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pet measurement of adenosine stimulated absolute myocardial blood flow for physiological assessment of the Coronary Circulation
Journal of Nuclear Cardiology, 2012Co-Authors: Henry GewirtzAbstract:Considerable awareness has been raised of late of the need to reduce radiation exposure and control costs of x-ray and radionuclide imaging procedures. PET/CT cameras are now widely available and in conjunction with appropriate radionuclides and commercially available software make quantitative measurement of absolute MBF feasible for routine clinical practice. Quantitative measurement of absolute MBF under condition of Coronary vasodilation permits independent assessment of the functional status of each of the three major Coronary perfusion zones and so obviates the need for rest MBF determination in the great majority of cases. Coronary microvascular function also may be assessed in this same way. Thus, the stress-only protocol with quantitative PET measurement of MBF provides essential information required for clinical decision making related to need for catheterization and intervention for patients with known or suspected ischemic heart disease. Moreover, the single PET determination of maximal MBF in contrast to the usual rest/stress procedure addresses both safety and cost concerns. The present review focuses on: (1) quantitative PET measurements of myocardial blood flow for physiological assessment of the Coronary Circulation and (2) the value and potential limitations of performing stress only imaging in the clinical context.
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adaptive responses of Coronary Circulation and myocardium to chronic reduction in perfusion pressure and flow
American Journal of Physiology-heart and Circulatory Physiology, 1994Co-Authors: I Mills, J T Fallon, D Wrenn, H Sasken, W Gray, J Bier, Daniel M Levine, S Berman, M Gilson, Henry GewirtzAbstract:We tested the hypothesis that chronic reduction in perfusion pressure and flow in the Coronary Circulation induces a state of myocardial "hibernation" characterized not only by a steady-state reduction in myocardial O2 consumption (MVO2) but also by evidence of persistent dilator reserve of the distal vasculature. Biochemical and morphological changes in the Coronary vasculature were also assessed. Experiments were conducted in swine with an extraluminal Coronary stenosis placed 4-32 wk before study. Stenosis reduced lumen diameter by approximately 80% at the time of final experimentation. Baseline, regional myocardial blood flow distal to the stenosis in both endocardial and epicardial layers was reduced vs. that of the normal zone. Vasodilator reserve persisted in both endocardial and epicardial layers of the stenosis zone. Flow increased in each layer in response to adenosine plus phenylephrine and failed to decline despite a marked reduction in perfusion pressure in response to adenosine alone. Regional MVO2 at baseline was reduced vs. historical controls without Coronary stenosis. Protein synthesis rate in Coronary vessels of the stenosis zone was reduced vs. that of the normal zone. Morphological responses of stenosis zone vessel walls were heterogeneous. Smaller microvessels exhibited mild hypertrophy of their walls, whereas walls of larger microvessels tended to atrophy. Thus chronic reduction in perfusion pressure and flow induces a state of myocardial hibernation characterized by a steady-state reduction in MVO2 in association with persistent dilator capacity. Biochemical and morphological changes occur in microvessel walls and may contribute to observed physiological responses.