Coronary Artery Perfusion Pressure Research Articles

VASOPRESSIN-INDUCED ST-ELEVATION MYOCARDIAL INFARCTION

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Vasopressin is commonly used to restore blood pressure in hyperdynamic hemodynamic states, thereby reducing catecholamine requirements. The effects of vasopressin are primarily caused by the rise in the mean arterial pressure (MAP) due to systemic vasoconstriction, which, depending on the infusion rate, can also produce notable vasoconstrictive effects on the coronary microvasculature thereby reducing coronary blood flow despite an increase in coronary perfusion pressure. Here we present an interesting case of vasopressin-induced ST-elevation myocardial infarction (STEMI) on postoperative day two of cardiac catheterization for initial STEMI. CASE PRESENTATION: A 67-year-old male with a past medical history of hypertension, hypothyroidism presented to the emergency department (ED) with the complaint of left shoulder pain. In the ED waiting room, the patient suddenly collapsed losing consciousness, and was found to be in cardiac arrest. ACLS protocol was immediately started and ROSC was achieved. An electrocardiogram (EKG) was performed which showed STEMI in the anterolateral leads. Code STEMI was activated, and the patient was taken for the cardiac catheterization where LAD stenosis was observed and stented. Post-procedure, the patient was transferred to Cardiac ICU, where an amiodarone drip was initiated for recurrent episodes of non-sustained ventricular tachycardia. The hospital course was further complicated with pneumonia leading to acute hypoxemic respiratory failure and septic shock. The patient was placed on norepinephrine and appropriate antibiotics. Vasopressin was added to reduce catecholamine requirements and to achieve a target MAP. On postoperative day two, the patient was noted to have ST elevation on the tele monitor, a twelve lead EKG confirmed anteroseptal STEMI. A left heart catheterization revealed a patent LAD stent with no new findings and recommendations were made to stop vasopressin infusion and to continue the rest of the treatment. The patient was successfully extubated to BiPAP, eventually made a slow and steady recovery, and was discharged home with follow-up appointments. DISCUSSION: It has been shown that the levels of vasopressin increase as part of the stress response, which has been shown to exert vasoconstrictive effects on the coronary arteries mainly in the non-epicardial vessels of the microcirculation. These high levels in states like myocardial infarction can lead to coronary slow phenomenon mediating ischemia-perfusion injury. CONCLUSIONS: In advanced distributive shock with accompanied cardiogenic shock state, utmost caution should be taken as the vasoconstrictor properties of vasopressin are not accompanied by positive inotropic qualities, which may depress cardiac function even further as a result of impaired coronary blood flow despite increased coronary artery perfusion pressure and in severe cases can lead to myocardial ischemia. REFERENCE #1: Nobian A, Mohamed A, Spyridopoulos I. The role of arginine vasopressin in myocardial infarction and reperfusion. Kardiol Pol. 2019 Oct 25;77(10):908–17. REFERENCE #2: Hauser B, Asfar P, Calzia E, Laporte R, Georgieff M, Radermacher P. Vasopressin in vasodilatory shock: is the heart in danger? Crit Care. 2008;12(2):132. REFERENCE #3: Asfar P, Radermacher P. Vasopressin and ischaemic heart disease: more than coronary vasoconstriction? Crit Care. 2009;13(4):169. DISCLOSURES: No relevant relationships by Mohammed Ali, source=Web Response No relevant relationships by Humayun Anjum, source=Web Response No relevant relationships by Rahul Dadhwal, source=Web Response No relevant relationships by Salim Surani, source=Web Response

Supra-coronary aortic banding improves right ventricular function in experimental pulmonary arterial hypertension in rats by increasing systolic right coronary artery perfusion.

Pulmonary arterial hypertension (PAH) results in right ventricular (RV) dysfunction owing, in part, to RV ischemia. The relative contribution of RV microvascular rarefaction vs reduced right coronary artery perfusion pressure (RCA-PP) to RV ischemia remains unknown. We hypothesize that increasing RCA-PP improves RV function in PAH by increasing RV systolic perfusion. Supra-coronary aortic banding (SAB) or sham surgery was performed on male Sprague-Dawley rats. Seven to ten days later, rats received either monocrotaline (MCT; 60mg/kg) or saline. After 1month, echocardiography, cardiac catheterization, 99m Tc-sestamibi single-photon emission computed tomography (SPECT) and microsphere infusion studies were performed. The RV was harvested for measurement of hypertrophy (RVH), fibrosis and immunoblotting, and the lung was harvested for pulmonary artery (PA) histology. Supra-coronary aortic banding increased systolic pressures in proximal aorta and systolic RCA-PP in SAB+MCT vs MCT rats (114±12 vs 5±9mmHg), without altering diastolic RCA-PP. SAB+MCT rats had improved RV function vs MCT rats, evident from their significantly increased cardiac output (CO), RV free wall (RVFW) thickening, tricuspid annular plane systolic excursion (TAPSE) and RV-PA coupling indices. RV-PA coupling indices and CO correlated directly with systolic RCA-PP. RV perfusion was increased in SAB+MCT vs MCT rats and correlated well with CO; whereas microvascular rarefaction was unaltered. SAB+MCT rats had less RVH and fibrosis and lower PA pressures vs MCT rats. SAB+MCT rats had significantly lower RV pyruvate kinase muscle isoform 2/1 ratios than MCT rats, consistent with restoration of oxidative metabolism. A SAB-induced increase in systolic RCA-PP improves RV perfusion and function in MCT rats. Maintaining systolic RCA perfusion can preserve RV function in PAH.

Arterial Stiffness in the Heart Disease of CKD.

CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

Therapie des akuten und chronischen Rechtsherzversagens

Acute or chronic right ventricular failure is an often misdiagnosed cause of cardiopulmonary insufficiency. In addition to clinical symptoms or laboratory testing, echocardiography and invasive hemodynamic measurement by means of right-heart catheterization are essential for diagnosis and treatment control. In case of acute right ventricular failure, adequate symptomatic treatment of the life-threatening situation is important. Main issues are maintenance of coronary artery perfusion pressure and myocardial oxygen delivery as well as reduction of right ventricular afterload. In persistent right ventricular failure extracorporeal or intracorporeal assist devices are increasingly used as bridging or destination therapy. On along-term basis, the targeted therapy of the underlying disease is crucial.

The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure.

The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension. RV hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation, fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis, adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-brain natriuretic peptide levels, troponin release, elevated catecholamine levels, RV dilatation, and late gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of G-protein receptor kinase-mediated downregulation, desensitization, and uncoupling of β-adrenoreceptors. RV ischemia may result from capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a forkhead box protein O1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of pyruvate dehydrogenase kinase, fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis, adrenergic signaling, and phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary vascular disease.

Experiencia actual con óxido nítrico inhalado en la insuficiencia de ventrículo derecho tras cirugía cardiaca

La insuficiencia del ventrículo derecho en el perioperatorio de los pacientes sometidos a cirugía cardiaca suele tener relación con hipertensión pulmonar y es un factor de riesgo independiente de muerte en esta cirugía. Tras la circulación extracorpórea, aumentan las resistencias vasculares pulmonares, que condicionan un aumento de la poscarga del ventrículo derecho y su insuficiencia. Para su tratamiento, se necesitan fármacos que disminuyan la hipertensión pulmonar sin disminuir la presión arterial sistémica ni la presión de perfusión coronaria. El óxido nítrico inhalado produce vasodilatación pulmonar selectiva, y sería el fármaco ideal en esta situación clínica. En este artículo se hace una revisión del óxido nítrico inhalado y se expone la experiencia actual en el tratamiento de situaciones clínicas con alto riesgo de insuficiencia ventricular derecha, como la cirugía cardiaca con circulación extracorpórea, la tromboendarterectomía pulmonar, el trasplante cardiaco y pulmonar, y la implantación de asistencia circulatoria ventricular izquierda. Perioperative right ventricular failure in patients undergoing cardiac surgery is usually associated with pulmonary hypertension and is an independent risk factor for death with this type of surgery. Following cardiopulmonary bypass, pulmonary vascular resistance increases, which leads to greater right ventricular afterload and the risk of right ventricular failure. Treatment must involve a drug that can reduce pulmonary hypertension without decreasing either systemic arterial pressure or coronary artery perfusion pressure. Inhaled nitric oxide is a selective pulmonary vasodilator that could be ideal in this clinical context. The aims of this article were to review the use of inhaled nitric oxide and to report recent experience with the substance in the treatment of clinical conditions that involve a high risk of right ventricular failure, such as cardiac surgery with cardiopulmonary bypass, pulmonary thromboendarterectomy, heart and lung transplantation, and implantation of left ventricular assist devices.

Left ventricular strain, rotation, and torsion as markers of acute myocardial ischemia

This study investigates how tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) describe regional myocardial deformation during controlled reductions of left anterior descending (LAD) coronary artery perfusion pressure. In eight anesthetized pigs, a shunt with constrictor was installed from the brachiocephalic artery to the LAD. Data were obtained with open shunt, followed by four degrees of stenosis (S1-S4) of increasing severity: S1, ∼15%; S2, ∼35%; S3, ∼50%; and S4, ∼60% reductions of LAD perfusion pressure. At each situation, microspheres for perfusion measurements were injected and left ventricular (LV) short- and long-axis cineloops were recorded. In the anterior wall, radial, circumferential, and longitudinal one-layer STE strain, one-layer radial TDI strain, and three-layer radial TDI and STE strain were measured. LV peak mean rotation was measured at six equidistant levels from apex to base (in 7 pigs). LV torsion was calculated from end-systolic mean rotation. With open shunt, three-layer TDI analysis showed a transmural strain gradient with no perfusion gradient. Perfusion, one-layer TDI strain, and strain in the mid- and subendocardium from three-layer TDI were reduced at S2 (P < 0.05). STE strain was not affected until S3 (P < 0.05). Peak mean rotation, increasing toward the apex, decreased at the three apical levels at S4 (P < 0.05). LV torsion did not decrease (P = 0.26). In conclusion, TDI strain detected dysfunction already with minor changes in global hemodynamics, whereas STE strain was first reduced with moderate changes. LV peak mean rotation was not reduced until severe reduction of LAD perfusion pressure, but remained increasingly counterclockwise toward the apex. LV torsion remained unaffected by ischemia.

Part 13: pediatric basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Part 13: pediatric basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Coronary blood flow and perfusion pressure during coronary angiography in patients with ongoing mechanical chest compression: A report on 6 cases

Patients with pulseless electrical activity or refractory ventricular fibrillation have a very bad prognosis. Coronary angiography and angioplasty may be required to restore an effective circulation, but this must be performed whilst chest compressions are continued. The LUCAS chest compression device is suitable for this purpose. So far there are no reports on the effect of this device on coronary circulation in humans. We monitored the coronary perfusion pressure assessed invasively as the difference between the diastolic pressures at the coronary ostium and right atrium, and compared these pressures with coronary flow graded using the TIMI scale in 6 patients. In 4 out of 6 we found a satisfactory coronary artery perfusion pressure and TIMI grade 3 flow (normal) on coronary angiography. Two of these patients survived the first 24 h. Two patients did not have a satisfactory perfusion pressure and adequate flow rate was not seen.

Arterial pulse wave velocity, inflammatory markers, pathological GH and IGF states, cardiovascular and cerebrovascular disease

Blood pressure (BP) measurements provide information regarding risk factors associated with cardiovascular disease, but only in a specific artery. Arterial stiffness (AS) can be determined by measurement of arterial pulse wave velocity (APWV). Separate from any role as a surrogate marker, AS is an important determinant of pulse pressure, left ventricular function and coronary artery perfusion pressure. Proximal elastic arteries and peripheral muscular arteries respond differently to aging and to medication. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, peaks during early adulthood, declining at 14% per decade. Levels of insulin-like growth factor-I (IGF-I) are at their peak during late adolescence and decline throughout adulthood, mirror imaging GH. Arterial endothelial dysfunction, an accepted cause of increased APWV in GH deficiency (GHD) is reversed by recombinant human (rh) GH therapy, favorably influencing the risk for atherogenesis. APWV is a noninvasive method for measuring atherosclerotic and hypertensive vascular changes increases with age and atherosclerosis leading to increased systolic blood pressure and increased left ventricular hypertrophy. Aerobic exercise training increases arterial compliance and reduces systolic blood pressure. Whole body arterial compliance is lowered in strength-trained individuals. Homocysteine and C-reactive protein are two inflammatory markers directly linked with arterial endothelial dysfunction. Reviews of GH in the somatopause have not been favorable and side effects of treatment have marred its use except in classical GHD. Is it possible that we should be assessing the combined effects of therapy with rhGH and rhIGF-I? Only multiple intervention studies will provide the answer.

Apolipoprotein A-IMilano/POPC complex attenuates post-ischemic ventricular dysfunction in the isolated rabbit heart

Irreversible myocardial injury is a potential consequence of coronary artery revascularization. Reperfusion leads to the production of oxidized products that can damage myocardium. High-density lipoproteins (HDL) are effective at removing oxidized lipids. We hypothesized that a synthetic HDL preparation, comprising recombinant apolipoprotein A-IMilano (apoA-IM) complexed with 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) (apoA-IM/POPC) would protect the heart from reperfusion injury. The ex vivo model consisted of rabbit hearts perfused by the Langendorff method. Hearts were equilibrated with Krebs–Henseleit buffer (10min), pretreated with either apoA-IM/POPC (0.45mg/mL) or vehicle (10min), subjected to global ischemia (30min) and reperfused for 60min. ApoA-IM/POPC (n=7) prevented the left ventricular end-diastolic pressure elevation observed in the vehicle group (n=6) at the end of reperfusion (p<0.05). During reperfusion, coronary artery perfusion pressure increased in the controls (p<0.001), but not with apoA-IM/POPC. ApoA-IM/POPC reduced the release of creatine kinase at the end of the ischemic period (p<0.001). It also reduced cardiac left ventricle muscle lipid hydroperoxides by 46% (p<0.05). Direct comparison of the antioxidant potential indicated that recombinant apoA-IM was much more potent than apoA-I in attenuating low-density lipoprotein oxidation. Electron microscopy showed that apoA-IM/POPC prevented mitochondrial granulation, disorganization and sarcomere contraction band formation indicative of reperfusion injury.The apoA-IM/POPC complex thus appears to reduce reperfusion injury under global ischemic conditions, and may therefore have therapeutic application in the reduction of myocardial ischemia.

Exercise Training and Coronary Resistance in Spontaneously Hypertensive Rats

1097 Exercise training induces alterations in the intrinsic control of coronary vascular resistance. However, the mechanism of such adaptations remains unclear, particularly in hypertension. PURPOSE: To examine how exercise training impacts coronary resistance in a model of spontaneous hypertension. Methods: Nineteen, 16 week old, female spontaneously hypertensive rats (SHR) were randomly placed into a lowintensity treadmill exercise training group (EX, n = 9; 20 m/min, 1 hr/day, 5 d/wk for 12 weeks) or kept sedentary (SED, n = 10). Coronary resistance was measured with a retrograde-perfused Langendorff preparation. All hearts were perfused with Krebs- Henseleit buffer (gassed at 95% O2 and 5% CO2 with 2 mM Ca2+) at 37 degrees C and held at constant flow (16 ml/min). Isovolumic left ventricular end-diastolic pressure was fixed at 10 mmHg and all hearts were equilibrated for 15 min. Results: At 28 weeks, systolic blood pressure was similar between groups. Langendorff-derived left ventricular developed pressure (SED; 176 ± 9.7 vs. 174 ± 5.5 mmHg, p = 0.4) was also similar between SED and EX. However, despite similar levels of isovolumic cardiac work, coronary artery perfusion pressure (SED; 139 ± 9.8 vs. EX; 111 ± 7.8 mmHg, p<0.05) and coronary resistance (SED; 8.7 ± 0.6 vs. EX; 7.2 ± 0.59 mmHg/ml, p<0.05) were greater in SED hearts than EX hearts. Conclusion: Our data is consistent with normotensive models, showing that exercise training favorably impacts the coronary vasculature. These training-induced changes occurred despite similar workloads in both the SED and EX groups. These findings suggest that the alterations in the control of coronary resistance produced by exercise training in hypertension may not be metabolically driven, but rather are mediated by endothelial and/or neurohumoral mechanisms.

Cardiac donor management: another point of view

The shortage of suitable donor hearts is an important limiting factor in heart transplantation and continues to produce discussion about adequate donor management with regard to graft quality. Recent recommendations, such as limiting the doses of catecholamines for maintenance therapy of cardiac donors, have causes up to two thirds of cardiovascular surgeons to refuse a heart graft from a donor treated with dopamine doses greater than 10 μg/kg/min although endogenous catecholamines may cardiac and pulmonary complications in organ donors, these conditions may be treated using similar agents. Perhaps it is the magnitude of the endogenous catecholamine surge that produces the pathology; thereafter, the levels, may quickly decrease to the point of catecholamine depletion at the receptor level so that exogenous administration is not deleterious and even can have beneficial effects. In the hemodynamic management of organ donors, administration of catecholamines with alpha and beta-1 effects may be needed in sufficient doses to reverse the loss of sympathetic tone at the vascular and cardiac level. Hemodynamic responses display a great individual variability; therefore, a maximal dose should not be set. Catecholamine administration increases coronary artery perfusion pressure, thus optimizing the cardiac performance. Furthermore, it is posible that immunomodulatory effects of catecholamines influence acute allograft rejection rates.

Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists.

For decades the pulmonary circulation was not considered as important as the systemic (“greater”) circulation. However, pulmonary hypertension can arise because of many diseases of the heart and lung. Therefore, increasing efforts in research have been undertaken leading to a profound increase in un

Experimental off-pump coronary artery revascularization with adenosine-enhanced reperfusion

Objective: Although beating heart coronary artery bypass grafting has recently gained popularity, it eliminates the protective strategies (ie, cardioplegia) developed for use in conventional cardiac operations. We recently introduced the technique of perfusion-assisted direct coronary artery bypass to perfuse the grafted vessels during multivessel off-pump coronary artery bypass grafting. In the present study we tested the hypothesis that intracoronary reperfusion with the cardioprotective agent adenosine during simulated perfusion-assisted direct coronary artery bypass attenuates reperfusion injury. Methods: In anesthetized dogs the heart was exposed, and the left anterior descending coronary artery was ligated for 75 minutes. Reperfusion was achieved through a catheter in the left anterior descending coronary artery by means of a computer-controlled pump. Intracoronary left anterior descending coronary artery perfusion pressure was continuously matched to mean arterial blood pressure. In one group (adenosine group) 10 μmol/L adenosine was added to the blood during the first 30 minutes of reperfusion, whereas another group (vehicle group) received a comparable volume of saline solution. Results: During the first 30 minutes of reperfusion, blood flow through the left anterior descending coronary artery was significantly greater (P <.05) in the adenosine group than in the vehicle group (150.6 ± 21.9 vs 50.2 ± 11.3 mL/min at 15 minutes of reperfusion). Although there were no group differences in postischemic wall motion, infarct size was significantly smaller in the adenosine group than in the vehicle group (11.1% ± 3.0% vs 28.0% ± 4.0% of area at risk, P <.05). Myeloperoxidase activity in the necrotic tissue, an index of neutrophil accumulation, tended to be lower in the adenosine group than in the vehicle group (58.6 ± 14.2 vs 91.0 ± 21.6 ΔAbsUnits · min–1 · g–1 tissue). In isolated postischemic left anterior descending coronary artery rings, the maximal relaxation response to the endothelium-dependent vasodilator acetylcholine was significantly greater in the adenosine group than in the vehicle group (97.9% ± 5.6% vs 64.7% ± 6.5%, P <.05). Conclusion: This novel reperfusion strategy for off-pump coronary artery bypass grafting can be used not only in cases requiring multiple grafting but also to attenuate necrosis and endothelial dysfunction in acute evolving infarction. (J Thorac Cardiovasc Surg 2001;121:570-9)

Catecholamines in cardiac arrest: role of alpha agonists, beta-adrenergic blockers and high-dose epinephrine

Once initial defibrillation has failed, the advanced cardiac life support (ACLS) guidelines for cardiopulmonary resuscitation (CPR) recommend periodic intravenous administration of epinephrine to increase coronary artery perfusion pressure (CPP) via arterial vasoconstriction to [1]. During prolonged cardiac arrest coronary perfusion pressure and forward blood flow are the major determinants of successful resuscitation, for when CPP is too low, successful resuscitation is unlikely. When the CPP is marginal, resuscitation may be possible; however, 24-h survival is unlikely [2]. When CPR is able to generate CPP above 30 mmHg associated with adequate forward blood flow as reflected in an adequate end-tidal CO2 the 24-h survival rate is greatly improved [2]. The American Heart Association ACLS guidelines recommend epinephrine as the pressor agent of choice during prolonged CPR [1]. These recommendations are based on now classic works [2–8]. Yet, studies have accumulated over the years that have raised concern that epinephrine’s beta-adrenergic effect may increase the myocardial oxygen consumption of the fibrillating heart and predispose to post-defibrillation dysfunction and cardiac arrhythmias [9–16]. Added to this concern was the finding that endogenous catecholamine concentrations are high during ventricular fibrillation even in the absence of epinephrine administration [11]. Ditchey and associates found, in a canine ventricular fibrillation cardiac arrest model, that the balance between myocardial oxygen supply and demand was improved by the administration of propranolol and phenylephrine, an exogenous selective alpha-agonist [9]. The limitations of these studies, however, is that high-dose epinephrine was used and survival was not evaluated. High-dose epinephrine administered during resuscitation initially appeared to be useful, producing higher perfusion pressures, but high-dose epinephrine has not been shown in clinical trials [17,18] nor in some experimental trials [12,13] to improve survival. Studies from our laboratory found that high-dose epinephrine resulted in postresuscitative tachycardia, systemic hypertension and greater early mortality relative to the standard dose [12]. Other laboratories have also documented adverse effects of high-dose epinephrine when given during CPR, including post-resuscitation hyperadrenergic state [14], myocardial necrosis [15], and worsened post-arrest cardiomyopathy [16]. Although pure alpha-agonists have not been shown to be superior to epinephrine [19–22], one could speculate that a combination of an alpha-adrenergic agonist and a beta-blocker might improve hemodynamics during CPR and thus improve long-term survival while avoiding the post resuscitation problem of excessive beta stimulation. * Correspnding author. Tel.: +1-520-626-7383.

Part 8: Advanced Challenges in Resuscitation

Part 8: Advanced Challenges in Resuscitation

Chronic cardiac denervation affects the speed of coronary vascular regulation.

We tested the hypothesis that the rate of adaptation of coronary metabolic vasodilatation and autoregulation is modulated by the cardiac nerves. Anaesthetised dogs (seven innervated (control) and seven with denervated hearts) were subjected to controlled pressure perfusion of the left main coronary artery. Heart rate was controlled by pacing. The steady state autoregulation curves and metabolic regulation curves were similar in the two groups. A sudden increase or decrease in heart rate was associated with a faster response (22% shorter half-times) in the innervated than the denervated dogs (P < 0.001). A sudden increase or decrease in coronary arterial perfusion pressure was associated with a slower response (24% longer half-times) in the innervated than the denervated hearts (P < 0.005). We conclude that the speed of response to metabolic and perfusion pressure changes is partly mediated by cardio-cardiac reflexes. Reflex coronary vasodilatation appears to reinforce the metabolic vasodilatation of a heart rate increase and oppose the vasoconstriction in response to increased perfusion pressure.

Reviparin-sodium prevents complement-mediated myocardial injury in the isolated rabbit heart.

The cytoprotective action of reviparin-sodium (LU-47311: Clivarin), a low-molecular-weight heparin, was examined in an ex vivo model of complement-mediated myocardial injury. The effective concentration of reviparin was determined by using an in vitro rabbit erythrocyte-lysis assay using 4% normal human plasma. Reviparin (0.01-2.73 mg/ml) reduced erythrocyte lysis in a concentration-dependent manner. Subsequently, 0.91 mg/ml of reviparin was evaluated in an ex vivo rabbit isolated-heart model of human complement-mediated injury. Hearts perfused in the presence of 0.91 mg/ml of reviparin (n = 10) demonstrated significant preservation of ventricular function compared with vehicle-treated hearts (n = 10), as evidenced by coronary artery perfusion pressure, left ventricular developed pressure, and left ventricular end-diastolic pressure. A reduction in myocyte creatine kinase release was observed in reviparin-treated hearts compared with controls. Myocardial injury in vehicle-treated hearts was associated with an increased assembly of the membrane-attack complex, as determined by immunohistochemical localization of C5b-9 neoantigen. Reviparin decreased fluid-phase Bb formation detected in the lymphatic drainage of plasma-perfused hearts. The results of this study demonstrate that reviparin inhibits complement-mediated myocardial injury as assessed in an ex vivo experimental model of complement activation.

Activation of protein kinase C by angiotensin II decreases beta 1-adrenergic receptor responsiveness in the rat heart.

Cardiac beta-adrenergic receptors are the primary driving force for the enhancement of contractility in response to sympathetic stimulation. Angiotensin II influences cardiac function by modulating sympathetic activity and by activating cardiac angiotensin II receptors. The aim of this study was to determine whether activation of cardiac angiotensin II receptors modulates the responsiveness of the heart to beta-adrenergic receptor activation. Male Sprague-Dawley rats were anesthetized and the hearts isolated and perfused with oxygenated Krebs-Henseleit buffer (KHB). Coronary artery perfusion pressure, left ventricular pressure (LVP), left ventricular dP/dtmax, and heart rate (HR) were measured. Bolus administration of the beta-adrenergic receptor agonists, isoproterenol, dobutamine, and salbutamol, produced dose-related increases in LVP, LV dP/dt(max), and HR. Addition of angiotensin-II (10-100 nM) to the KHB slightly increased coronary perfusion pressure but did not alter baseline LVP, LV dP/dt(max), or HR. Angiotensin II reduced the increase in LVP, LV dP/dt(max), and HR elicited by isoproterenol and dobutamine but did not affect responses to salbutamol. The inhibitory effect of angiotensin II was blocked by the AT1-receptor antagonist, losartan, and the protein kinase C inhibitor, calphostin C (50 nM). Activation of protein kinase C with phorbol-12, 13-dibutyrate (PDBu; 10 nM) reduced cardiac responses to all three agonists, although the effects were less on responses elicited by salbutamol. These data suggest that activation of protein kinase C by angiotensin II decreases the responsiveness of the rat heart to beta 1-adrenergic stimulation and that angiotensin II-mediated protein kinase C activation may differ from that activated by phorbol esters.