Cardiac effects of the extract and active components of radix stephaniae tetrandrae. II. Myocardial infarct, arrhythmias, coronary arterial flow and heart rate in the isolated perfused rat heart.

The primary purpose of the present study was to compare the cardioprotective effects of the extract from radix stephaniae tetrandrae (RST) and its individual compounds, tetrandrine (Tet) and fanchinoline (Fan). Secondly, we also compared the cardiac effects of the individual compounds and the RST extract with those of verapamil, a classical Ca2+ channel blocker. The Langendorff isolated perfused rat heart preparation was used. Regional ischaemia and reperfusion was employed to induce myocardial infarct and arrhythmia. Infarct, arrhythmia, heart rate and coronary artery flow were determined in hearts treated with vehicle, RST extract, Tet, Fan, or verapamil. It was found that RST extract, of which only 9% was Tet, and Tet alone produced equally potent ameliorating effects on arrhythmia and infarct induced by ischaemia and reperfusion without further inhibiting ischaemia-reduced heart rate and coronary artery flow. Fan had no effects on arrhythmia and infarct induced by ischaemia and reperfusion; but it induced S-T segment elevation and further reduced heart rate and coronary artery flow during ischaemia. Verapamil also ameliorated the effects of ischaemia and reperfusion on arrhythmia and infarct. It should be noted that 1 microM verapamil, that produced comparable effects on infarct and arrhythmia to the RST extract and Tet, further inhibited heart rate during ischaemia. The results indicate that the RST extract produces equally potent cardioprotective and anti-arrhythmic effects as Tet alone. Both RST extract and Tet may be better choices for the treatment of arrhythmia and infarct induced by myocardial ischaemia and reperfusion than the classical Ca2+ channel blocker, verapamil as they do not further reduce heart rate during ischaemia.     

Ventricular tachycardia due to cardiac ischaemia: assessment by exercise electrocardiography

Although ventricular tachycardia is a well-known complication of myocardial ischaemia and may be provoked by exercise, many patients may appreciate only the angina and be unaware of the unduly rapid heart rate that precipitates it. Exercise testing is needed to show this arrhythmia and to enable treatment to be started.Twenty-three patients were found to have chronic ischaemic heart disease complicated by ventricular tachycardia. Six patients with old myocardial infarction had ventricular tachycardia at rest which required conversion to sinus rhythm; 17 patients developed ventricular tachycardia only when they exercised. In 12 of these 17 patients coronary angiography showed disease of the anterior descending branch of the left coronary artery; other vessels were usually also affected. Although beta-adrenergic blocking drugs increased exercise tolerance, ventricular tachycardia still occurred when the heart rate on exercise reached a level similar to that before treatment. In five patients coronary artery bypass surgery was performed because of angina and exercise-induced ventricular tachycardia. Exercise tolerance was increased in all three patients who underwent exercise tests after operation, and in two of these patients, both of whom were known to have patent grafts, ventricular tachycardia was abolished.If part of the beneficial effect of coronary bypass surgery is preventing life-threatening ventricular arrhythmias it is essential to detect these, and ambulatory monitoring and stress testing have a complementary role.     

Biomechanical rationale of coronary artery bypass grafting of multivessel disease

The biomechanical model of human coronary arteries was modified for improving the quality of diagnosis and surgical treatment for coronary heart disease. The problem of hemodynamics in the left coronary artery with multivessel bed disease – 45% stenosis of the anterior descending branch and 75% stenosis of the circumflex branch – was particularly considered. Numerical simulation of the coronary arterial bypass of the main trunk was carried out to estimate the functional condition of the coronary arteries after restoring myocardial blood supply by surgery.     

Robotic totally endoscopic multivessel coronary artery bypass grafting: procedure development, challenges, results

Closed-chest totally endoscopic coronary artery bypass grafting (TECAB) is feasible using robotic technology. During the early phases, TECAB was restricted to single bypass grafts to the left anterior descending artery system. Because most patients referred for coronary artery bypass surgery have multivessel disease, development of endoscopic multiple bypass grafting is mandatory. Experimental work on multivessel TECAB was carried out in the early 2000s, and first clinical cases were already performed. With further technological development of operating robots, double, triple, and quadruple TECAB has become feasible both on the arrested heart and on the beating heart. To date, 161 cases of multivessel TECAB using the da Vinci telemanipulation systems are published in the literature. The main advances enabling multivessel TECAB were the availability of a robotic endostabilizer for beating heart procedures and increased surgeon skills using remote access heart-lung machine perfusion and endo-cardioplegia. Both internal mammary arteries can be harvested and both radial artery and vein graft can be used in multivessel TECAB. Y-grafting and sequential grafting are feasible. Multivessel endoscopic surgical revascularization can be combined with percutaneous coronary interventions in advanced hybrid coronary revascularization. Time requirements for multivessel TECAB are significant, and conversion rates to larger thoracic incisions are higher than those observed for single-vessel TECAB. Clinical short- and long-term outcomes, however, seem to meet the standards of open coronary bypass surgery through sternotomy. The main advantages of multivessel TECAB are a completely preserved sternum, use of double internal mammary artery even in risk groups, and a remarkably short recovery time.     

Cold pressor test in diagnosis of coronary artery disease: echophonocardiographic method.

The cold pressor test was used to induce myocardial ischaemia in patients with coronary artery disease and the rise in left ventricular filling pressure used as the index of myocardial ischaemia. Left ventricular filling pressure was derived from a non-invasive echophonocardiographic method. A study group of 19 consecutive patients with chest pain underwent the cold pressor test before coronary angiography. Eighteen responded with a rise in filling pressure exceeding 30% and, of these, 17 had serious coronary artery disease (three single vessel, one two vessel, and 13 triple vessel disease; one had coronary artery spasm only). The remaining patient, who showed no rise in filling pressure, did not have coronary artery disease. None of 15 normal controls showed a rise greater than 5% (patients with coronary artery disease versus normal controls p less than 0.001). The cold pressor test would be suitable for patients who cannot or should not exercise and may be combined with exercise electrocardiograms to improve the information content, as it uses a different marker of myocardial ischaemia.     

Myocardial ischaemia following electrical stimulation of the left circumflex coronary artery in sheep: a role for thromboxane A2?

The electrical stimulation model of thrombus formation was tested on rabbit carotid artery and adapted to sheep left circumflex coronary artery (LCCA). LCCA blood flow, mean arterial pressure (MAP), heart rate (HR) and ECG were monitored continuously and arterial and coronary venous blood samples were taken for radioimmunoassay of thromboxane B2. Stimulation of the LCCA mimicked acute myocardial infarction; reduction in LCCA blood flow preceded a fall in MAP and appearance of ECG abnormalities. Thromboxane B2 levels rose by 126% 35 min after stimulation. These findings support the proposal by other authors that thromboxane plays an important role in the pathogenesis of acute myocardial infarction.     

Anomalous origin of the left coronary artery connected to the pulmonary artery in a 31-year-old woman

Anomalous origin of the left coronary artery connected to the pulmonary artery (ALCAPA) is a rare congenital defect with a high mortality rate in infancy if left untreated. It may cause myocardial ischaemia and can lead to myocardial infarction, mitral dysfunction, cardiac arrhythmias, heart failure and sudden death. Without operation, survival into adulthood is rare. We report clinical findings, diagnostic characteristics and therapy in a 31-year-old woman with ALCAPA and preserved left ventricular function.     

Dobutamine stress magnetic resonance imaging suffices for the demonstration of myocardial ischaemia and viability

We report three patients in whom dobutamine stress magnetic imaging (DS-MRI) was essential in assessing myocardial ischaemia. Two patients were referred to the cardiologist because of chest pain. Patient A had typical exertional angina and a normal resting electrocardiogram (ECG). Patient B had typical exercise-induced angina and had recently experienced an attack of severe chest pain at rest for 15 minutes. The ECG showed a complete left bundle branch block (LBBB). Patient C was referred for heart failure of unknown origin. There were no symptoms of chest pain during rest or exercise. Echocardiography in this patient demonstrated global left ventricular (LV) dilatation, systolic dysfunction and a small dyskinetic segment in the inferior wall. In all these patients exercise stress testing had failed to demonstrate myocardial ischaemia. Patients A and C produced normal findings whereas in patient B the abnormal repolarisation due to pre-existent LBBB precluded a diagnosis of ischaemia.Breath-hold DS-MRI was performed to study LV wall motion and wall thickening at rest through increasing doses of dobutamine. A test was considered positive for myocardial ischaemia if wall motion abnormalities developed at high-dose levels of the drug (20 μg/kg/min or more with a maximum of 40 μg/kg/min) in previously normal vascular territories or worsened in a segment that was normal at baseline. Recovery of wall thickening in a previously hypokinetic or akinetic segment at a low dose of dobutamine (5-10 μg/kg/min) was taken as proof of viability.Patients A and B developed hypokinesia progressing into akinesia at high-dose dobutamine in the anteroseptal area of the LV indicative of ischaemia. These findings were corroborated by coronary angiography demonstrating severe coronary artery disease which led to coronary artery bypass grafting (CABG) in patient A and balloon angioplasty in patient B. In patient C global recovery of LV contractions during low-dose dobutamine was followed by hypokinesia in the inferoseptal area during high-dose dobutamine. This biphasic response indicates myocardial viability as well as ischaemia. CABG was carried out because of multiple stenoses in the left coronary artery. Post-operatively LV function normalised.DS-MRI is a valuable method for detecting myocardial ischaemia and viability in patients with suspected coronary artery, and can be applied in every hospital with MRI equipment at its disposal.     

Additive value of dobutamine stress echocardiography in patients with an anomalous origin of a coronary artery

An anomalous origin of a coronary artery (AOCA) is the second most common cause of non-traumatic sudden cardiac death in young athletes. Patients with a malignant course of an AOCA of the right coronary artery only need surgical correction when myocardial ischaemia is detected. An AOCA and its malignant or benign course can be detected by coronary angiography, coronary computed tomography or cardiac magnetic resonance imaging. Detection of ischaemia can be more difficult since even a negative maximal-effort stress ECG does not exclude a potential lethal coronary anomaly. Also, there are no case series or trials showing sensitivity or specificity for any form of ischaemia detection for AOCA in the literature. Although not described previously in adults, dobutamine stress echocardiography was previously described in a paediatric population with AOCA. We are the first to describe ischaemia detection by dobutamine stress echocardiography in three adult patients with an AOCA of the right coronary artery who were subsequently referred for surgery.

Electronic supplementary material

The online version of this article (doi: 10.1007/s12471-014-0648-3) contains supplementary material, which is available to authorized users.     

Precision Incision: Robotic Coronary Revascularization via 3.9-cm Minithoracotomy

ABSTRACT: Coronary artery bypass grafting remains the treatment choice for coronary artery disease; but sternotomy, the most commonly used approach, compromises its benefits with postoperative morbidity, higher complication rates, and prolonged length of hospital stay. Despite this, minimally invasive and robotic-assisted technology has not been adopted or widely embraced because supporting literature on robotic-assisted coronary artery bypass grafting is extremely limited. Since 2005, the cardiothoracic surgical team at our institution has been developing and maturing an effective method using robotic harvesting of the left internal mammary artery (LIMA) and beating heart surgery through a minithoracotomy for coronary revascularization. This surgical technique involves precisely placing the robotic endoscopic port immediately over the left anterior descending (LAD) artery target site. The robotically harvested LIMA is secured to the epicardium at the LAD target, the robotic instruments are removed, and the endoscopic port site is enlarged slightly greater than 1 cm to become the minithoracotomy and allow for LIMA-to-LAD anastomosis. The other two robotic ports are used to complete the procedure without a need for additional incisions. This standardized method has been used in more than 750 patients, and since 2009, the last 377 consecutive non-rib-spreading minithoracotomy incisions measured a median of 3.9 cm (mean [SD], 4.16 [1.2748] cm; range, 2.3-12.0 cm). This "How I Do It" article describes our methods in detail and associated robotic nuances.     

Rodent Working Heart Model for the Study of Myocardial Performance and Oxygen Consumption

Isolated working heart models have been used to understand the effects of loading conditions, heart rate and medications on myocardial performance in ways that cannot be accomplished in vivo. For example, inotropic medications commonly also affect preload and afterload, precluding load-independent assessments of their myocardial effects in vivo. Additionally, this model allows for sampling of coronary sinus effluent without contamination from systemic venous return, permitting assessment of myocardial oxygen consumption. Further, the advent of miniaturized pressure-volume catheters has allowed for the precise quantification of markers of both systolic and diastolic performance. We describe a model in which the left ventricle can be studied while performing both volume and pressure work under controlled conditions. In this technique, the heart and lungs of a Sprague-Dawley rat (weight 300-500 g) are removed en bloc under general anesthesia. The aorta is dissected free and cannulated for retrograde perfusion with oxygenated Krebs buffer. The pulmonary arteries and veins are ligated and the lungs removed from the preparation. The left atrium is then incised and cannulated using a separate venous cannula, attached to a preload block. Once this is determined to be leak-free, the left heart is loaded and retrograde perfusion stopped, creating the working heart model. The pulmonary artery is incised and cannulated for collection of coronary effluent and determination of myocardial oxygen consumption. A pressure-volume catheter is placed into the left ventricle either retrograde or through apical puncture. If desired, atrial pacing wires can be placed for more precise control of heart rate. This model allows for precise control of preload (using a left atrial pressure block), afterload (using an afterload block), heart rate (using pacing wires) and oxygen tension (using oxygen mixtures within the perfusate).     

Age-related cardiovascular responses of rats to coronary artery ligation

The cardiovascular responses of rats of different ages, ranging from 4-15 weeks (body weight 115-490 g), to acute left coronary artery ligation under pentobarbitone anaesthesia were studied. In older animals, the responses included the occurrence of ventricular tachycardia and/or fibrillation, decrease in blood pressure, and a slight increase in heart rate. On the contrary, younger rats exhibited atrioventricular block followed by ventricular arrest, and decreases in both blood pressure and heart rate. The findings demonstrate the existence of age-related cardiovascular responses to acute myocardial ischaemia in rats, and suggest that 10-15-week-old male Sprague-Dawley rats are suitable experimental animals for producing early ventricular arrhythmias by acute coronary artery ligation.     

Oxidative stress in myocardial ischaemia reperfusion injury: a renewed focus on a long-standing area of heart research

Advances in the treatment of coronary artery disease have seen a significant drop in mortality and morbidity particularly amongst patients with acute myocardial infarction (MI). In particular, percutaneous trans-luminal balloon angioplasty (PTCA) with stenting to re-open atherosclerotic coronary arteries has yielded marked improvement in clinical outcome for patients with acute MI. Furthermore, with the advent of drug-eluting stents occurrence rates for coronary artery restenosis, one common clinical problem associated with angioplasty and stent deployment, have declined markedly. However, coronary restenosis in diabetic patients remains an on-going problem. The success of drug-eluting stents has seen a renewed focus on myocardial ischaemia reperfusion (IR) injury as this represents one area of research where many questions remain unanswered. In particular, the relationship between myocardial IR injury and decreased myocardial micro-vasculature re-flow post PTCA (that ultimately leads to poor clinical outcome and myocardial damage/dysfunction) is one area of research with the potential to decrease current complication rates further in patients suffering myocardial IR injury sustained during MI. This review discusses the role for oxidative stress, oxidant source(s) and both gene regulation and stem-cell therapy as potential strategic targets in the ischaemic myocardium, with the ultimate aim of providing significant cardioprotection in the setting of acute MI.     

An ovine model of postinfarction dilated cardiomyopathy in animals with highly variable coronary anatomy

Studies on cardiac regeneration require large mammalian models of dilated cardiomyopathy (DCM) after acute myocardial infarction (AMI), and pig and sheep models are increasingly used in this field of preclinical research. Given the large interindividual variability in ovine left anterior descending artery (LAD) anatomy, protocols based on the coronary arteries to be ligated often lead to significant variation in infarct sizes and hence to heterogeneous results, ranging from no ventricular remodeling to acute, lethal left ventricular (LV) failure. We designed an ovine model of postinfarction DCM based on estimated infarct size rather than on a predetermined menu of coronary artery ligatures. In seven adult sheep we induced an anterolateral AMI of approximately 25% of the LV mass by ligating the branches of the LAD that, by visual inspection, would lead to such an infarct size. In 10 to 12 weeks, LV end-diastolic volume more than doubled and LV end-systolic volume almost tripled. LV ejection fraction decreased dramatically, as did LV percent fractional shortening and LV percent wall thickening. Infarct size (planimetry) was approximately 25% of the LV endocardial surface. We conclude that in sheep, an anterolateral AMI of approximately 25% of the LV mass--regardless of the coronary branches ligated to attain that infarct size--results in a model of postinfarction DCM that may prove useful in preclinical research on myocardial regeneration.     

Prevalence of asymptomatic myocardial ischaemia in diabetic subjects.

OBJECTIVE--To compare the prevalence of silent myocardial ischaemia associated with coronary artery disease in diabetic subjects with that in controls of similar age and sex. DESIGN--A controlled study in which subjects with positive findings on exercise electrocardiography, 24 hour electrocardiographic recording, or dynamic thallium scintigraphy (diabetics only) underwent coronary angiography. SETTING--Academic medical centre; referral based cardiology clinic. SUBJECTS--136 Diabetic subjects, of whom 72 (33 women, 39 men (mean age 46.0] were insulin dependent and 64 (19 women, 45 men (mean age 49.3] non-insulin dependent. 80 Controls matched for age and sex; all were clients of the Occupational Health Service of Oulu University Central Hospital or the State Occupational Health Service Station in Oulu in whom diabetes had been excluded by a glucose tolerance test. INTERVENTIONS--Any subject showing signs of myocardial ischaemia was referred for cardiac catheterization. MAIN OUTCOME MEASURES--Exercise electrocardiography and 24 hour electrocardiographic recording were regarded as positive if there were ST depressions of greater than or equal to 1 mm that were planar or downsloping and persisted for 0.08 seconds after the J point. Thallium tomographic imaging. With cardiac catheterisation, coronary artery lesions were classified as significant in half or more of the vessel lumen was narrowed, or insignificant if such narrowing was less than half. RESULTS--40 (29%) diabetes and four (5%) controls had positive results in one or more of the non-invasive tests. Coronary angiography was performed on 34 of the diabetics (six refused); 12 had significant coronary artery narrowing; seven had unimportant atherosclerosis; 15 had patent coronary arteries. Among the controls only one had unimportant atherosclerosis; the other three had patent arteries. CONCLUSIONS--These results confirm the high prevalence of asymptomatic myocardial ischaemia in diabetics. Non-invasive screening of diabetic subjects, however, does not seem justified because of the low preset probability of the presence of the disease and the inaccuracy of the available test methods.     

犬冠状动脉阻力的胆碱能调节

本实验在麻醉开胸犬,采用冠状动脉左旋支恒流灌注,于搏动的和心室纤颤(VF)的心脏,研究了电刺激迷走神经(VNS)及冠状动脉内注入乙酰胆碱(ACh)对冠状动脉阻力的影响。当 VNS 和冠脉内给 ACh 时,(1)心肌内小冠状动脉阻力显著减低,而心外膜大冠状动脉阻力并无明显变化;(2)冠状动脉左旋支总阻力的减低幅度在 VF 的心脏比在搏动的心脏显著减小。以上结果表明,迷走-ACh 扩张冠脉的作用主要是舒张心肌内小冠状动脉,并可通过减低心肌收缩力而间接降低冠状动脉阻力。     

The discovery of the selective If current inhibitor ivabradine (Procoralan): a new therapeutic approach to ischemic heart disease

Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries and its prevalence is predicted to grow with the current aging of the population in these countries. In spite of the rapid pace of progress and increasing use of myocardial revascularization procedures, in particular percutaneous coronary interventions, the medical treatment of coronary artery disease has lost none of its relevance in the majority of patients, though conventional drugs have their limitations and the pharmacological approach to ischemic heart disease needs to be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement in quality of life. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most ischemic episodes, but also as an independent predictor of mortality, inhibition of the pacemaker If current in view of inducing a direct and selective decrease in heart rate represents an ideal conceptual target and an attractive therapeutic approach to coronary artery disease. The screening of original benzocycloalkane compounds at the Servier Research Institute resulted in the selection of ivabradine (Procoralan) for clinical development. Preclinical data showed that ivabradine inhibits the If current originating in the sinus node, induces a selective reduction in heart rate both at rest and during exercise, preserves myocardial contractility, atrioventricular conduction and ventricular repolarization and prevents exercise-induced myocardial ischemia as effectively as a b-blocker while offering better protection of regional myocardial contractility. These data were confirmed in humans, in particular the anti-ischemic efficacy of ivabradine, at least as effective as that of a b-blocker in patients with stable angina. Large ongoing clinical trials are seeking to assess the therapeutic value of ivabradine in ischemic heart failure and its potential for improving the prognosis of coronary artery disease by reducing mortality and the occurrence of major cardiovascular events.     

Dynamic curvature strongly affects wall shear rates in a coronary artery bifurcation model

This study was motivated by the need for a better understanding of coronary artery blood flow patterns and their possible role in atherosclerosis formation. Of particular interest in this study was the effects of the dynamic deformation due to myocardial contraction on wall shear rate patterns in the coronary arteries. A better understanding of these effects on wall shear rate in a bifurcation geometry and an evaluation of the importance of these effects was desired. A three-dimensional computer model of a bifurcation lying on the surface of a sphere with time-varying radius of curvature was employed to simulate the motion and deformation of the arteries. The results indicated low mean shear rates along the myocardial wall and very high shear rate variations (over 100% of the static mean shear rate) along the outer wall. The results obtained using a quasi-static analysis were found to underestimate the dynamic wall shear rate variation along the myocardial and outer walls. It was concluded that dynamic geometry effects are important in determining sites of low mean and oscillating wall shear that have been associated with atherogenesis in curved, bifurcating arteries.     

The Pathogenesis of Human Myocardial Infarction

Coronary arteriography, dissection of the coronary arteries and histopathological examination of the heart were carried out in 150 autopsies to study the effect of coronary narrowing and occlusion, of the presence of collaterals, and of coronary artery predominance on the development of myocardial infarction. The thrombosis rate was related to the severity of coronary sclerosis. The development of collaterals was not enhanced by coronary sclerosis and occlusion, and collaterals did not protect the myocardium against reinfarction. Coronary occlusion was regularly demonstrable in recent myocardial infarct cases. The association of atrial and posterior ventricular infarcts was explained by occlusion of their common arterial branch. The interdependence between coronary sclerosis, thrombosis and myocardial infarction in human autopsy material emphasizes the importance of mural coronary artery disease in the genesis of coronary occlusion and myocardial infarction, and it is at variance with statistical data and experimental results.     

Revascularization in the acute coronary syndromes

Coronary heart disease is the leading cause of death worldwide, and occurs when the coronary arteries are unable to supply adequate oxygenated blood to the myocardium, which in turn can lead to ischemia and infarction of myocardial tissue. There are three options for revascularization in the setting of acute coronary syndromes. In select patients, coronary artery bypass surgery remains an option. Thrombolytics were initially the mainstay of therapy, which has now shifted to angioplasty, with or without stents, when readily available. Revascularization has been demonstrated to improve patient outcomes, and has evolved rapidly in the recent past.