Sympathetic control of the coronary circulation during trigeminal nerve stimulation in humans.

PURPOSE: We sought to investigate the sympathetic mechanism controlling coronary circulation during trigeminal nerve stimulation in healthy women. METHODS: The protocol consisted of 3 min of trigeminal nerve stimulation (TGS) with cold stimuli to the face, in two conditions: (1) control and ß-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin). RESULTS: Thirty-one healthy young subjects (women: n = 13; men: n = 18) participated in the study. By design, TGS decreased heart rate (HR), and increased blood pressure (BP) and cardiac output (CO). Before the ß-blockade coronary blood velocity (CBV-Δ1.4 ± 1.3 cm s-1) increased along with the decrease of coronary vascular conductance index (CVCi-Δ-0.04 ± 0.04 cm s-1 mmHg-1) during TGS and the ß-blockade abolished the CBV increase and a further decrease of CVCi was observed with TGS (Δ-0.06 ± 0.07 cm s-1 mmHg-1). During the α-blockade condition before the blockade, the CBV increased (Δ0.93 ± 1.48 cm s-1) along with the decrease of CVCi (Δ-0.05 ± 1.12 cm s-1 mmHg-1) during TGS, after the α-blockade CBV (Δ0.98 ± cm s-1) and CVCi (Δ-0.03 ± 0.06 cm s-1 mmHg-1) response to TGS did not change. CONCLUSION: Coronary circulation increases during sympathetic stimulation even with a decrease in heart rate.

Recovery of the cardiac autonomic nervous and vascular system after maximal cardiopulmonary exercise testing in recreational athletes.

OBJECTIVE: The body's adaptation to physical exercise is modulated by sympathetic and parasympathetic (vagal) branches of the autonomic nervous system (ANS). Heart rate variability (HRV), the beat-to-beat variation of the heart, is a proxy measure for ANS activity, whereas blood pressure (BP) is an indicator for cardiovascular function. Impaired vagal activity and lower BP is already described after exercise. However, inconsistent results exist about how long vagal recovery takes and how long post-exercise hypotension persists. Therefore, the aim of this study was to assess HRV and BP 1 h after maximal cardiopulmonary exercise testing (CPET). PATIENTS AND METHODS: HRV (Polar RS800CX), peripheral and central BP (Mobil-O-Graph®) were prospectively studied in 107 healthy volunteers (47 female, median age 29.0 years) in supine position, before and 60 min after maximal CPET. RESULTS: One hour after terminating CPET measures of HRV were still impaired and post-exercise BP was significantly reduced suggesting an improved vascular function compared to pre levels. HRV parameters post-exercise were 34.7% (RMSSD), 67.2% (pNN50), 57.2% (HF), and 42.7% (LF) lower compared to pre-exercise levels (for all p < 0.001). Median reduction in BP was 5 mmHg for systolic BP (p < 0.001), and 4 mmHg for diastolic BP (p = 0.016) and central systolic post-exercise (p = 0.005). CONCLUSIONS: One hour after terminating strenuous exercise, autonomic nervous regulation seems to be postponed which is reflected in reduced HRV, whereas the early recovery of the vasculature, post-exercise hypotension, is still preserved over the recovery period of 1 h.

Anatomical visualization of neural course and distribution of anterior ascending aortic plexus.

The aim of this study was to document the detailed anatomy of neural course and distribution on the anterior ascending aorta, to identify the high and low density areas of the anterior ascending aortic plexus for further understandings in cardiovascular surgery. The embalmed hearts of 42 elderly individuals were submacroscopically and microscopically examined, after excluding any that were macroscopically abnormal. With its origins in the anterior ascending aortic plexus, the right coronary plexus substantially innervated the right coronary artery, the right atrium and ventricle, and the sinus node. The intensive neural area extending from 10 mm lateral to the interatrial groove below the pericardial reflection as far as the right coronary artery opening contained almost all the right coronary plexus in 61.3% of patients, and more than 40.9% of the total nerve volume of the anterior ascending aortic plexus. Our findings suggest that the most superior and lateral area on the ascending aorta show the lowest neural density of right coronary component in the anterior ascending aortic plexus and the high density areas are invisible in right lateral field of view as seen in the right trans-axillary MICS approach.

A mathematical model of coronary blood flow control: simulation of patient-specific three-dimensional hemodynamics during exercise.

This work presents a mathematical model of the metabolic feedback and adrenergic feedforward control of coronary blood flow that occur during variations in the cardiac workload. It is based on the physiological observations that coronary blood flow closely follows myocardial oxygen demand, that myocardial oxygen debts are repaid, and that control oscillations occur when the system is perturbed and so are phenomenological in nature. Using clinical data, we demonstrate that the model can provide patient-specific estimates of coronary blood flow changes between rest and exercise, requiring only the patient's heart rate and peak aortic pressure as input. The model can be used in zero-dimensional lumped parameter network studies or as a boundary condition for three-dimensional multidomain Navier-Stokes blood flow simulations. For the first time, this model provides feedback control of the coronary vascular resistance, which can be used to enhance the physiological accuracy of any hemodynamic simulation, which includes both a heart model and coronary arteries. This has particular relevance to patient-specific simulation for which heart rate and aortic pressure recordings are available. In addition to providing a simulation tool, under our assumptions, the derivation of our model shows that ß-feedforward control of the coronary microvascular resistance is a mathematical necessity and that the metabolic feedback control must be dependent on two error signals: the historical myocardial oxygen debt, and the instantaneous myocardial oxygen deficit.

Coronary veins determine the pattern of sympathetic innervation in the developing heart.

Anatomical congruence of peripheral nerves and blood vessels is well recognized in a variety of tissues. Their physical proximity and similar branching patterns suggest that the development of these networks might be a coordinated process. Here we show that large diameter coronary veins serve as an intermediate template for distal sympathetic axon extension in the subepicardial layer of the dorsal ventricular wall of the developing mouse heart. Vascular smooth muscle cells (VSMCs) associate with large diameter veins during angiogenesis. In vivo and in vitro experiments demonstrate that these cells mediate extension of sympathetic axons via nerve growth factor (NGF). This association enables topological targeting of axons to final targets such as large diameter coronary arteries in the deeper myocardial layer. As axons extend along veins, arterial VSMCs begin to secrete NGF, which allows axons to reach target cells. We propose a sequential mechanism in which initial axon extension in the subepicardium is governed by transient NGF expression by VSMCs as they are recruited to coronary veins; subsequently, VSMCs in the myocardium begin to express NGF as they are recruited by remodeling arteries, attracting axons toward their final targets. The proposed mechanism underlies a distinct, stereotypical pattern of autonomic innervation that is adapted to the complex tissue structure and physiology of the heart.

Characterisation and distribution of human coronary artery innervation.

BACKGROUND: A detailed understanding of the sympathetic innervation of coronary arteries is relevant to facilitate the development of novel treatment approaches. AIMS: This study aimed to quantitatively examine periarterial innervation in human epicardial coronary arteries. METHODS: Coronary arteries with adjacent epicardial adipose tissue were excised along the left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA) from 28 body donors and examined histologically. Immunofluorescence staining was performed to characterise sympathetic nerve fibres. RESULTS: A total of 42,573 nerve fibres surrounding 100 coronary arteries (LMCA: n=21, LAD: n=27, LCx: n=26, RCA: n=26) were analysed. The nerve fibre diameter decreased along the vessel course (median [interquartile range]): (proximal 46 µm [31-73], middle 38 µm [26-58], distal 31 µm [22-46]; p<0.001), with the largest nerve fibre diameter along the LMCA (50 µm [31-81]), followed by the LAD (42 µm [27-72]; p<0.001). The total nerve fibre density was highest along the RCA (123 nerves/cm² [82-194]). Circumferentially, nerve density was higher in the myocardial tissue area of the coronary arteries (132 nerves/cm² [76-225]) than in the epicardial tissue area (101 nerves/cm² [61-173]; p<0.001). The median lumen-nerve distance was smallest around the LMCA (2.2 mm [1.2-4.1]), followed by the LAD (2.5 mm [1.1-4.5]; p=0.005). CONCLUSIONS: Human coronary arteries are highly innervated with sympathetic nerve fibres, with significant variation in the distribution and density. Understanding these patterns informs pathophysiological understanding and, potentially, the development of catheter-based approaches for cardiac autonomic modulation.

Innervation of the coronary arteries and its role in controlling microvascular resistance.

The coronary circulation plays a crucial role in balancing myocardial perfusion and oxygen demand to prevent myocardial ischemia. Extravascular compressive forces, coronary perfusion pressure, and microvascular resistance are involved to regulate coronary blood flow throughout the cardiac cycle. Autoregulation of the coronary blood flow through dynamic adjustment of microvascular resistance is maintained by complex interactions among mechanical, endothelial, metabolic, neural, and hormonal mechanisms. This review focuses on the neural mechanism. Anatomy and physiology of the coronary arterial innervation have been extensively investigated using animal models. However, findings in the animal heart have limited applicability to the human heart as cardiac innervation is generally highly variable among species. So far, limited data are available on the human coronary artery innervation, rendering multiple questions unresolved. Recently, the clinical entity of ischemia with non-obstructive coronary arteries has been proposed, characterized by microvascular dysfunction involving abnormal vasoconstriction and impaired vasodilation. Thus, measurement of microvascular resistance has become a standard diagnostic for patients without significant stenosis in the epicardial coronary arteries. Neural mechanism is likely to play a pivotal role, supported by the efficacy of cardiac sympathetic denervation to control symptoms in patients with angina. Therefore, understanding the coronary artery innervation and control of microvascular resistance of the human heart is increasingly important for cardiologists for diagnosis and to select appropriate therapeutic options. Advancement in this field can lead to innovations in diagnostic and therapeutic approaches for coronary artery diseases.

Anatomy of blood microcirculation in the pig epicardial ganglionated nerve plexus.

Embolization of coronary arteries and their terminal arterioles causes ischemia of all tissues distributed within a cardiac wall including the intrinsic cardiac ganglionated nerve plexus (ICGP). The disturbed blood supply to the ICGP causes chronic sympathetic activation with succeeding atrial and ventricular arrhythmias. This study analyses the anatomy of microcirculation of epicardial nerves and ganglia using the hearts of 11 domestic pigs. Our findings demonstrate that thicker epicardial nerves are normally supplied with blood via 12 epineural arterioles penetrating the endoneurium regularly along a nerve, and forming an endoneurial capillary network, which drains the blood into the myocardial blood flow. The mean diameter of intraneural capillaries was 7.2 ± 0.2 µm, while the diameters of arterioles were 25.8 ± 0.7 µm and involved 45 endothelial cells accompanied by circular smooth muscle cells. Usually, two or three arterioles with a mean diameter of 28.9 ± 1.7 µm supplied blood to any epicardial ganglion, in which arterioles proceeded into a network of capillaries with a mean diameter of 6.9 ± 0.3 µm. Both the epicardial nerves and the ganglia distributed near the porta venarum of the heart had tiny arterioles that anastomosed blood vessels from the right and the left coronary arteries. The density of blood vessels in the epicardial nerves was significantly lesser compared with the ganglia. Our electron microscopic observations provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation. STRUCTURED ABSTRACT: This study details the anatomy of microcirculation of epicardial nerves and ganglia, from which intracardiac nerves and bundles of nerve fibers extend into all layers of the atrial and ventricular walls in the most popular animal model of experimental cardiology and cardiac surgery - the domestic pig. Our findings provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation.

Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing.

The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and ß-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and ß-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure.

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20-50 µg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

The coronary circulation in exercise training.

Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. In large animals, EX increases capillary exchange capacity through angiogenesis of new capillaries at a rate matched to EX-induced cardiac hypertrophy so that capillary density remains normal. However, after EX coronary capillary exchange area is greater (i.e., capillary permeability surface area product is greater) at any given blood flow because of altered coronary vascular resistance and matching of exchange surface area and blood flow distribution. The improved coronary capillary blood flow distribution appears to be the result of structural changes in the coronary tree and alterations in vasoreactivity of coronary resistance arteries. EX also alters vasomotor reactivity of conduit coronary arteries in that after EX, α-adrenergic receptor responsiveness is blunted. Of interest, α- and ß-adrenergic tone appears to be maintained in the coronary microcirculation in the presence of lower circulating catecholamine levels because of increased receptor responsiveness to adrenergic stimulation. EX also alters other vasomotor control processes of coronary resistance vessels. For example, coronary arterioles exhibit increased myogenic tone after EX, likely because of a calcium-dependent PKC signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, EX augments endothelium-dependent vasodilation throughout the coronary arteriolar network and in the conduit arteries in coronary artery disease (CAD). The enhanced endothelium-dependent dilation appears to result from increased nitric oxide bioavailability because of changes in nitric oxide synthase expression/activity and decreased oxidant stress. EX also decreases extravascular compressive forces in the myocardium at rest and at comparable levels of exercise, mainly because of decreases in heart rate and duration of systole. EX does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. While there is evidence that EX can decrease the progression of atherosclerotic lesions or even induce the regression of atherosclerotic lesions in humans, the evidence of this is not strong due to the fact that most prospective trials conducted to date have included other lifestyle changes and treatment strategies by necessity. The literature from large animal models of CAD also presents a cloudy picture concerning whether EX can induce the regression of or slow the progression of atherosclerotic lesions. Thus, while evidence from research using humans with CAD and animal models of CAD indicates that EX increases endothelium-dependent dilation throughout the coronary vascular tree, evidence that EX reverses or slows the progression of lesion development in CAD is not conclusive at this time. This suggests that the beneficial effects of EX in CAD may not be the result of direct effects on the coronary artery wall. If this suggestion is true, it is important to determine the mechanisms involved in these beneficial effects.

Tyrosine hydroxylase immunoreactivity as indicator of sympathetic activity: simultaneous evaluation in different tissues of hypertensive rats.

Vasomotor control by the sympathetic nervous system presents substantial heterogeneity within different tissues, providing appropriate homeostatic responses to maintain basal/stimulated cardiovascular function both at normal and pathological conditions. The availability of a reproducible technique for simultaneous measurement of sympathetic drive to different tissues is of great interest to uncover regional patterns of sympathetic nerve activity (SNA). We propose the association of tyrosine hydroxylase immunoreactivity (THir) with image analysis to quantify norepinephrine (NE) content within nerve terminals in arteries/arterioles as a good index for regional sympathetic outflow. THir was measured in fixed arterioles of kidney, heart, and skeletal muscle of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) (123 ± 2 and 181 ± 4 mmHg, 300 ± 8 and 352 ± 8 beats/min, respectively). There was a differential THir distribution in both groups: higher THir was observed in the kidney and skeletal muscle (∼3-4-fold vs. heart arterioles) of WKY; in SHR, THir was increased in the kidney and heart (2.4- and 5.3-fold vs. WKY, respectively) with no change in the skeletal muscle arterioles. Observed THir changes were confirmed by either: 1) determination of NE content (high-performance liquid chromatography) in fresh tissues (SHR vs. WKY): +34% and +17% in kidney and heart, respectively, with no change in the skeletal muscle; 2) direct recording of renal (RSNA) and lumbar SNA (LSNA) in anesthetized rats, showing increased RSNA but unchanged LSNA in SHR vs. WKY. THir in skeletal muscle arterioles, NE content in femoral artery, and LSNA were simultaneously reduced by exercise training in the WKY group. Results indicate that THir is a valuable technique to simultaneously evaluate regional patterns of sympathetic activity.

Myocardial blood flow and cardiac sympathetic innervation in young adults late after arterial switch operation for transposition of the great arteries.

BACKGROUND: The arterial switch operation (ASO) for repair of transposition of the great arteries (TGA) requires transection of the great arterial trunks and re-implantation of the coronary arteries into the neoaortic root resulting in cardiac sympathetic denervation which may affect myocardial blood flow (MBF) regulation. The aims of the present study were to evaluate sympathetic (re-)innervation in young adults after ASO and its impact on MBF. METHODS: Twelve patients (age 22.5 ±â€¯2.6 years) after ASO for TGA in the neonatal period and ten healthy controls (age 22.0 ±â€¯1.7 years) were included. Positron emission tomography (PET) was used for measuring cardiac sympathetic innervation with [11C]meta-hydroxyephedrine (mHED) and MBF with [15O]H2O PET at rest, during adenosine stimulation, and during sympathetic stimulation with cold pressor test. Cold pressor-induced MBF response capacity was calculated as maximal global MBF over peak rate-pressure product multiplied by 10'000. RESULTS: Global [11C]mHED uptake was significantly lower in patients compared to controls (7.0 ±â€¯2.3 versus 11.8 ±â€¯2.1%/min, p < 0.001). Global MBF was lower in patients compared to controls at rest and during adenosine-induced hyperemia (0.66 ±â€¯0.08 versus 0.82 ±â€¯0.15 ml/min/g, p = 0.005; 2.23 ±â€¯1.19 versus 3.36 ±â€¯1.04 ml/min/g, p = 0.030, respectively). Interestingly, MBF during cold pressor test did not differ between patients and controls (0.99 ±â€¯0.20 versus 1.07 ±â€¯0.16 ml/min/g, p = 0.330). However, cold pressor-induced MBF response capacity was significantly lower for patients as compared to controls (1.09 ±â€¯0.35 versus 1.44 ±â€¯0.39 ml/g/10,000 mmHg, p = 0.040). CONCLUSIONS: With only partial sympathetic re-innervation of the coronary arteries, maximal dilator capacity of the coronary microvasculature and cold pressor-induced MBF response capacity remain substantially impaired in young adults after ASO compared to healthy controls.

[Heart innervation in rats (an immunohistochemical study)].

The aims of the present study were to investigate the structure of the nervous apparatus in different heart regions using the immunohistochemical methods. The study was performed in Wistar rats (n - 5). For selective staining of synaptic structures, synaptophysin (Syn) demonstration was used, while neurofilament proteins (NF-M) were used to detect axonal neurofilaments. The innervation apparatuses in the heart were shown to be unevenly distributed. High density of Syn- and of NF-M-positive axons was found in the myocardium near the atrial sinus, vena cava superior and inferior, pulmonary veins, aorta, truncus pulmonalis, as well as in the deep layers of atrial myocardium, and in the myocardium of anterior and posterior ventricle walls. In the heart apex, within the ventricular myocardium, the density of immunopositive axons was low. Using the antibodies against Syn, only the synaptic terminals of the efferent postganglionic nerve fibers and of the parasympathetic vegetative nerve fibers were selectively demonstrated in the heart, as well as the pericellular synapses on the parasympathetic neurons of intracardiac ganglia. NF-M-immunopositive axons, unlike Syn-positive terminals, were found not only in the myocardium, but also in the epicardium and the endocardium within the same regions of the heart. The authors believe that these axons belong to afferent sensory and efferent preganglionic myelinated nerve fibres of PNS.

Evidence of relevant electrical connection between the left atrial appendage and the great cardiac vein during catheter ablation of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) triggers within the coronary sinus (CS)/great cardiac vein (GCV) and the left atrial appendage (LAA) have been recognized as nonpulmonary vein triggers of AF. OBJECTIVE: The aim of this study was to describe an electrical connection between the LAA and CS/GCV and its importance in achieving LAA electrical isolation (LAAEI). METHODS: A total of 488 consecutive patients undergoing catheter ablation for persistent or long-standing persistent AF who showed firing from the LAA and/or from the CS/GCV were enrolled in this multicenter prospective study. In all patients, potential defragmentation of the CS/GCV to achieve isolation and LAAEI was attempted with both endocardial and epicardial ablation. RESULTS: In 7% (n = 34) of these patients, after attempting endocardial LAAEI, the LAA was isolated during epicardial ablation in the GCV. In 8% (n = 39) of patients after attempting endocardial LAA isolation, the LAA was isolated during ablation along the endocardial aspect of the GCV. The presence of a venous branch connecting the GCV with the LAA was found in all these patients. In 23% (n = 112) of patients, the isolation of the LAA also isolated the GCV. In all these patients, LAA dissociated firing was present together with the CS/GCV recordings. CONCLUSION: These findings suggest the presence of a distinct electrical connection between the GCV and the LAA. The clinical relevance of our results requires further investigation. Ablation in the CS/GCV can result in inadvertent isolation of the LAA. Ablation of the GCV is relevant to achieve LAAEI. Considering the potential long-term implications, ablation in the distal CS/GCV should prompt assessment of LAA conduction.

Sympathectomy versus conventional treatment for refractory coronary artery spasm.

BACKGROUND: There is no clear consensus on the potential efficacy and indications for sympathectomy to prevent recurrence of vasospasm in patients with refractory coronary artery spasm (CAS). OBJECTIVE: To compare the clinical outcomes of sympathectomy with those of conventional treatment in patients with refractory CAS. PATIENTS AND METHODS: Patients with refractory CAS were randomly assigned to sympathectomy group (n = 37) or conventional treatment group (n = 42). The primary end point was a composite of major adverse cardiac event (MACE) episodes (including cardiac death, nonfatal myocardial infarction, unstable angina, heart failure, and life-threatening arrhythmia), and the secondary end point was death from any cause within 24 months after randomization. RESULTS: During the follow-up period of 24 months, the incidence of MACE in the sympathectomy and conventional treatment groups was 16.22 and 61.90%, respectively (P = 0.0001). All-cause death as the secondary end point occurred in zero and six (14.29%) patients, respectively (P = 0.0272). The Kaplan-Meier curve for MACE and all-cause death showed a significant between-group difference (log-rank test, P = 0.0013 and 0.0176, respectively). CONCLUSION: Compared with conventional treatment, sympathectomy significantly reduced the composite end point of MACE episodes and death from any cause in patients with refractory CAS by effectively preventing recurrence of vasospasm.

Topography of the porcine epicardiac nerve plexus as revealed by histochemistry for acetylcholinesterase.

The aim of the present study was to map the topography of the porcine epicardiac nerve plexus (ENP) and to re-examine the total number and distribution of the porcine intracardiac ganglia and neurons. Eleven juvenile pigs (Sus scrofa domestica, 3-4 weeks of age) were examined employing histochemistry for acetylcholinesterase to reveal the ENP on total hearts. The nerves entered porcine epicardium at five sites: (1) ventro-medially to the origin of the superior vena cava, (2) dorsally to the origin of the superior vena cava, (3) among the pulmonary veins, (4) dorso-medially to the origin of the left azygos vein, and (5) ventrally to the left pulmonary vein. Within the porcine epicardium, the nerves connected to the groups of the intrinsic ganglia and proceeded into the discrete atrial and ventricular regions via five topographical pathways (subplexuses). In general, the porcine left atrium received nerves by four subplexuses, left ventricle by three subplexuses, right atrium and right ventricle each by two subplexuses. The estimated total number of the intrinsic ganglia per porcine heart was 362+/-52. About 55% of ganglia per porcine heart were accumulated on the left atrium while 36% on the right atrium. The percentage of ganglia within porcine ventricular and para-aortic regions was 7.6% and 1.6%, respectively. On average, porcine heart contained about 12,000 intrinsic neurons. In summary, the results of the present study imply that (1) the porcine epicardiac nerves are grouped into distinct topographical pathways, and (2) the porcine atria contain significantly more intrinsic ganglia and neurons compared to the ventricles.

Hypoxia-induced vasodilation in the right coronary circulation of conscious dogs: role of adrenergic activation.

The role of adrenergic activation in the right coronary (RC) flow response to hypoxia has not been previously delineated, and limited information from left coronary studies is inconsistent. Seven dogs were instrumented with catheters implanted in the aorta and in the right ventricle to measure aortic pressure and right ventricular (RV) pressure, respectively. A flow transducer was placed around the RC artery to measure RC flow. After recovery from surgery, the dogs were exposed to systemic hypoxia in a Plexiglas chamber ventilated with N(2). Percent O(2) in the chamber was monitored, and blood samples and hemodynamic data were collected as chamber O(2) was progressively reduced to approximately 6%. The chamber was then opened, and the dog breathed room air. Phentolamine, 1 mg/kg, and propranolol, 2 mg/kg, were then administered via the RV catheter to achieve adrenergic blockade, and the hypoxia protocol was repeated. During hypoxia, arterial PO(2) progressively fell from 87+/-3 to 25+/-1 mmHg during untreated control condition and from 90+/-4 to 23+/-1 mmHg during adrenergic blockade. In the unblocked condition, hypoxia caused increases in aortic pressure, heart rate, RV pressure, and RV dP/dt(max). After adrenergic blockade, normoxic aortic pressure was reduced; heart rate and RV dP/dt(max) tended to be lower. Aortic pressure rose during hypoxia, but to lesser values than before blockade. Heart rate and RV dP/dt(max) also increased, but only at more severe hypoxia, and these values were less than before blockade. Normoxic flow and hypoxia-induced increases in RC flow and conductance were not altered by blockade. The relationship between RC conductance and RV triple product, an index of RV O(2) demand, was steeper after blockade. These findings indicate that in the normal, unblocked condition, RC flow during hypoxia is restrained by an adrenergic-mediated increase in RC vasomotor tone.

3D reconstruction of the porcine and equine pulmonary veins, supplemented with the identification of telocytes in the horse.

The myocardial sleeve of the porcine and equine pulmonary veins were histologically investigated and reconstructed three dimensionally. Moreover, the localization of neuron cell bodies at the veno-atrial junction and alongside the myocardial sleeve was light microscopically visualized to depict the organization of nerve, myocardial and fat tissue. Finally, the presence of telocytes inside the equine pulmonary veins was demonstrated by use of transmission electron microscopy. These structures are thought to play a role in the induction of atrial fibrillation, which is frequently seen in horses, while pigs are often used as a cardiovascular model in this context. This data fills in remaining gaps in the literature concerning the histological build-up of the pulmonary veins wall in pigs and horses. In-depth knowledge on the myocardial sleeve and its surrounding cell types are important to understand the possible outcome of an ablation therapy as an atrial fibrillation treatment. In pigs and horses, the layout of the pulmonary veins wall concerning these structures is comparable to humans. However, neuron cell bodies were recovered at the veno-atrial junction in both species but not alongside the myocardial sleeve in horses.

Adenine nucleotides and 5-hydroxytryptamine released by aggregating platelets inhibit adrenergic neurotransmission in canine coronary artery.

The purpose of this study was to determine the effect of vasoactive substances released by aggregating platelets on adrenergic neurotransmission in canine coronary arteries. Isometric tension was recorded in isolated ring segments of coronary artery denuded of endothelium and the release of [3H]norepinephrine was measured from strips of coronary artery preincubated with the radiolabeled transmitter. Transmural electrical field stimulation and exogenously added norepinephrine caused beta adrenergic relaxations of coronary rings contracted by prostaglandin F2 alpha. In coronary rings further contracted by the addition of aggregating platelets in numbers less than that present in blood, the response to electrical stimulation was inhibited and the sensitivity to norepinephrine reduced. Micromolar concentrations of adenosine diphosphate, adenosine triphosphate, and 5-hydroxytryptamine were released by platelets under these experimental conditions. The reduced response to electrical stimulation was in part due to inhibition of the stimulated release of [3H]-norepinephrine. The combination of the serotonergic antagonist, methiothepin, and the purinergic antagonist, theophylline, attenuated the inhibition of the responses of coronary rings; either antagonist alone failed to do so, but did significantly block the reductions caused by 5-hydroxytryptamine and adenosine diphosphate, respectively. In addition, only the combination of the two antagonists significantly attenuated the inhibition of norepinephrine release caused by platelets. These data suggest that both adenine nucleotides and 5-hydroxytryptamine are important mediators of the prejunctional and postjunctional inhibition of coronary beta adrenergic neurotransmission caused by platelets.