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.

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.

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.

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.

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.

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.

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.

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.

Regulation of Coronary Blood Flow.

The heart is uniquely responsible for providing its own blood supply through the coronary circulation. Regulation of coronary blood flow is quite complex and, after over 100 years of dedicated research, is understood to be dictated through multiple mechanisms that include extravascular compressive forces (tissue pressure), coronary perfusion pressure, myogenic, local metabolic, endothelial as well as neural and hormonal influences. While each of these determinants can have profound influence over myocardial perfusion, largely through effects on end-effector ion channels, these mechanisms collectively modulate coronary vascular resistance and act to ensure that the myocardial requirements for oxygen and substrates are adequately provided by the coronary circulation. The purpose of this series of Comprehensive Physiology is to highlight current knowledge regarding the physiologic regulation of coronary blood flow, with emphasis on functional anatomy and the interplay between the physical and biological determinants of myocardial oxygen delivery. © 2017 American Physiological Society. Compr Physiol 7:321-382, 2017.

Rare case of single coronary artery in a patient with liver cirrhosis.

We report here the case of a 58-year-old male presented with atypical chest pain, dyspnea and fatigue, with a medical history of liver cirrhosis and undergoing treatment with beta-blocker. The clinical exam was normal. The 12-lead electrocardiogram (ECG) showed normal heart rate, without repolarization changes. Transthoracic echocardiography revealed no wall motion abnormalities of the left ventricle, moderate tricuspid regurgitation with mild pulmonary hypertension and left ventricular hypertrophy. The biochemical markers for myocardial infarction were negative. He underwent coronary angiography that revealed a single coronary artery originating from the right coronary sinus of Valsalva.

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 vasomotor function in infarcted and remote myocardium after primary percutaneous coronary intervention.

OBJECTIVE: In patients with acute myocardial infarction (AMI), coronary vasomotor function is impaired in the myocardial territory supplied by the culprit artery and in remote myocardium supplied by angiographically normal vessels. The aim was to investigate the temporal evolution of coronary vasodilatory reserve in patients with AMI by use of [(15)O]H2O positron emission tomography, after successful percutaneous coronary intervention. METHODS: 44 patients with AMI and successful revascularisation by percutaneous coronary intervention were included. Subjects were examined 1 week and 3 months after AMI with [(15)O]H2O positron emission tomography to assess the coronary flow reserve (CFR). CFR was defined as the ratio of myocardial blood flow (MBF) during hyperaemia and rest. Additionally, 45 age-matched and sex-matched subjects underwent similar scanning procedures and served as controls. RESULTS: At baseline, CFR averaged 1.81±0.66 in infarcted myocardium versus 2.51±0.81 in remote myocardium (p<0.01). In comparison, CFR in the control group averaged 4.16±1.45 (p=0.001 vs both). During follow-up, the CFR increased to 2.74±0.85 in infarcted myocardium (p<0.01), and to 2.85±0.70 in remote myocardium (p<0.01). This was predominantly due to an increase in hyperaemic MBF, from 1.62±0.54 mL/min/g to 2.19±0.68 mL/min/g in infarcted myocardium (p<0.001), and 2.17±0.54 mL/min/g to 2.60±0.65 mL/min/g in remote myocardium (p<0.001). CONCLUSIONS: CFR in infarcted and remote myocardium is impaired 1 week after AMI. After 3 months vasomotor function partially recovers. However, as compared with control patients, MBF remains impaired in culprit and reference territories in patients with AMI. CLINICAL TRIAL REGISTRATION: NTR3164.

Prevention of ventricular arrhythmia complicating acute myocardial infarction by local cardiac denervation.

BACKGROUND: Augmentation of sympathetic nerve activity after acute myocardial infarction (AMI) contributes to fatal arrhythmia. In this study, we investigated whether local ablation of the coronary sinus (CS) and great cardiac vein (GCV) peripheral nerves could reduce ventricular arrhythmias (VA) in a canine AMI model. METHODS: Twenty-one anesthetized dogs were randomly assigned into the sham-operated, MI and MI-ablation groups, respectively. The incidence and duration of VA were monitored among different groups. The ventricular effective refractory period (ERP), the ERP dispersion and the ventricular fibrillation threshold (VFT) were measured during the experiments. Norepinephrine (NE) levels in CS blood and cardiac tissue were also detected in this study. RESULTS: The incidence and duration of VA in MI-ablation group were significantly reduced as compared to the MI dogs (p<0.05). Furthermore, local cardiac denervation drastically prolonged the ventricular ERP in the ischemia area, decreased the ERP dispersion, and reduced NE levels in CS blood (P<0.05). VFT also showed an increased trend in the AMI-ablation group. CONCLUSIONS: The results of this study indicate that, in the canine AMI model, local ablation of CS and GCV peripheral nerves reduces VA occurrence and improves ventricular electrical stability with no obvious effects on heart rate, mean arterial pressure and infarct size. This study suggests that local cardiac denervation may prevent ventricular arrhythmias complicating AMI.

Ethanol infusion in the vein of Marshall leads to parasympathetic denervation of the human left atrium: implications for atrial fibrillation.

OBJECTIVES: This study sought to determine whether ethanol infusion in the vein of Marshall (VOM) can ablate intrinsic cardiac nerves (ICN). BACKGROUND: ICN cluster around the left atrial epicardium and are implicated in the genesis of atrial fibrillation (AF). METHODS: Patients undergoing catheter AF ablation underwent adjunctive ethanol injection in the VOM. A multipolar catheter was introduced in the VOM and used for high-frequency stimulation (HFS), either as HFS with P-wave synchronized (SynchHFS), 30 pulses, 100 Hz (n = 8) or as HFS with 3 to 10 s bursts (BurstHFS), 33 Hz (n = 72) at 25 mA for 1-ms duration. Atrioventricular (AV) nodal conduction slowing (asystole >2 s or R-R interval prolongation >50%) and AF inducibility were assessed before and after VOM ethanol infusion. Up to 4 1-ml infusions of 98% ethanol were delivered via an angioplasty balloon in the VOM. RESULTS: SynchHFS induced AF in 8 of 8 patients. In 4 of 8 AF initiated spontaneously without VOM capture. No parasympathetic responses were elicited by SynchHFS. BurstHFS was performed in 32 patients undergoing de novo AF ablation (Group 1) and 40 patients undergoing repeat ablation (Group 2). Parasympathetic responses were found in all 32 Group 1 patients and in 75% of Group 2 patients. After VOM ethanol infusion, parasympathetic responses were abolished in all patients (both groups). There were no acute complications related to VOM ethanol infusion. CONCLUSIONS: The VOM contains ICN that connect with the AV node and can trigger AF. Retrograde ethanol infusion in the VOM reliably eliminates local ICN responses. The VOM is a vascular route for ICN-targeting therapies.

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.

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.