Changes In Coronary Perfusion Pressure Research Articles

Contribution of local metabolic control to coronary pressure-flow autoregulation

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. This study interrogated the local metabolic hypothesis, which proposes that myocardial oxygen tension, indexed by coronary venous PO 2 (CvPO 2 ), determines the degree of coronary pressure-flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which dobutamine-induced increases in myocardial oxygen consumption (MVO 2 ) under both normoxic and hypoxemic conditions, influences coronary autoregulatory capability. Experiments were performed on open-chest anesthetized swine during 20 mmHg stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg, via servo-controlled roller pump. Measurements were made in 3 conditions: a) normoxia (n = 7); b) normoxia with dobutamine (10 μg/kg/min, iv; n = 7); and c) hypoxemia (PaO 2 36-38 mmHg) plus dobutamine (n = 5). Under control-normoxic conditions, CvPO 2 decreased from 38 ± 2 to 22 ± 1 mmHg and coronary blood flow fell from 0.93 ± 0.15 to 0.32 ± 0.03 ml/min/g as CPP was reduced from 140 to 40 mmHg. Administration of dobutamine significantly increased heart rate (~60%; P < 0.001), but the combination of hypoxemia plus dobutamine did not further influence heart rate. Further, dobutamine with and without hypoxemia significantly increased MVO 2 (P < 0.001); however, CvPO 2 was reduced (P < 0.001) only in the presence of hypoxemia. Calculation of closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) was unaffected by dobutamine alone but tended to increase when dobutamine infusion was combined with reductions in PaO 2 ≤ 40 mmHg (P = 0.069). Additional analysis of the autoregulatory slope within this same CPP range revealed no differences between groups. However, there was a significant inverse association between Gc and CvPO 2 , measured at CPP of 100 mmHg, in the absence and presence of dobutamine-induced increases in MVO 2 ± hypoxemic conditions (P < 0.001, r = -0.722). The relationship of coronary resistance (CPP range of 120 to 60 mmHg) relative to respective CvPO 2 revealed that decreases in CvPO 2 were not associated with changes in coronary resistance until CvPO 2 fell below a relative threshold of ~ 25 mmHg (r = 0.88). These findings support the interpretation that the sensitivity of coronary autoregulatory behavior is directly coupled with the activation of local metabolic vasodilator pathways below a critical level of myocardial oxygenation. This work was supported by National Institutes of Health grant R01 HL158723. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oxygen-sensing pathways below autoregulatory threshold act to sustain myocardial oxygen delivery during reductions in perfusion pressure.

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. However, the mechanisms responsible for coronary autoregulation remain a fundamental and highly contested question. This study interrogated the local metabolic hypothesis of autoregulation by testing the hypothesis that hypoxemia-induced exaggeration of the metabolic error signal improves the autoregulatory response. Experiments were performed on open-chest anesthetized swine during stepwise changes in coronary perfusion pressure (CPP) from 140 to 40mmHg under normoxic (n = 15) and hypoxemic (n = 8) conditions, in the absence and presence of dobutamine-induced increases in myocardial oxygen consumption (MVO2) (n = 5-7). Hypoxemia (PaO2 < 40mmHg) decreased coronary venous PO2 (CvPO2) ~ 30% (P < 0.001) and increased coronary blood flow ~ 100% (P < 0.001), sufficient to maintain myocardial oxygen delivery (P = 0.14) over a wide range of CPPs. Autoregulatory responsiveness during hypoxemia-induced reductions in CvPO2 were associated with increases of autoregulatory gain (Gc; P = 0.033) but not slope (P = 0.585) over a CPP range of 120 to 60mmHg. Preservation of autoregulatory Gc (P = 0.069) and slope (P = 0.264) was observed during dobutamine administration ± hypoxemia. Reductions in coronary resistance in response to decreases in CPP predominantly occurred below CvPO2 values of ~ 25mmHg, irrespective of underlying vasomotor reserve. These findings support the presence of an autoregulatory threshold under which oxygen-sensing pathway(s) act to preserve sufficient myocardial oxygen delivery as CPP is reduced during increases in MVO2 and/or reductions in arterial oxygen content.

Abstract 260: Aortic Pulse Wave Characteristics and Coronary Blood Flow Responses to Plantar Flexion in Peripheral Arterial Diseases Patients

Peripheral arterial diseases (PAD) is an atherosclerotic occlusive disease in the periphery affecting 8-12 million U.S.adults. It has been reported that the PAD patients have attenuated coronary blood flow response to stress, however how the diseases influence aortic arterial pulse wave properties during exercise, and its relationship with coronary perfusion in this patient population is unknown. Accordingly, the primary aim of this study was to examine myocardial supply and demand relationship by investigating aortic pulse wave properties and their relationship with coronary perfusion during exercise in PAD. Methods: 13 PADpatients and 13 healthy (age, sex, BMI-matched) control subjects performed rhythmic plantar flexion for 14 minutes or until fatigue (30 contractions per minute). The workload started at 2 kg and increased by 1 kg every minute up to12 kg. Brachial (oscillometric cuff) and aortic (SphygmoCor, utilizing transfer function and brachial blood pressures) blood pressures were measured during supine rest and plantar flexion exercise as well as aortic pulse wave properties from derived-aortic pulse waveforms. On a separate visit, coronary blood flow velocity was measured non-invasively during rest and exercise. Results: Due to earlier arrival of reflected wave (140.9± 2.3 vs. 150.5± 3.4 ms; P =0.0289), baseline augmented pressure (15.9± 2.4 vs. 9.3± 1.7 mmHg; AP, P =0.0380), augmentation index (27.2± 2.7 vs. 19.1± 2.2 %; AI, P =0.0263), and cardiac wasted energy (4625± 590 vs. 2875± 491 s· dyne· cm 2 ; E w , P =0.0321) were greater compared to healthy control. During exercise, changes in aortic mean arterial pressure(21.90± 5.04 vs. 9.36± 2.20 mmHg; ΔaMAP, P =0.0041), end-systolic pressure (133.38± 4.85 vs. 111.46± 4.97 mmHg; ΔESP, P =0.0043), and the tension time index (1027± 216 vs. 504± 117 mmHg· S -1 · min -1 ; ΔTTI, P =0.0035) were significantly greater in PAD while ΔAI was not different. Intriguingly, despite the augmented TTI, the first and second peaks of CBV during exercise were not different between the groups leading to significantly attenuated subendocardial viability ratio responses to exercise (-34.66± 4.19 vs. -23.03± 3.37 %; ΔSEVR, P =0.0164). Conclusions: At this peak workload for PAD patients, the patients had a greater myocardial demand compared to healthy control. However, despite the increase in the myocardial demand and the accompanying increase in initial coronary perfusion pressure (ESP), CBV of PAD patients was not different from that seen in healthy control indicating limited myocardial supply during exercise in PAD. Consequently, PAD exhibited a greater mismatch of myocardial demand and supply at the peak workload. This suggests that, in PAD patients, there are mechanisms aside from changes in coronary perfusion pressure that limit myocardial supply during exercise (i.e. a greater coronary vascular tone and diastolic dysfunction).

Abstract 438: Synchronization of Chest Compressions During Pseudo Electro-Mechanical Dissociation Improves Blood Pressures Relative to Standard Chest Compressions

Introduction: The treatment of pseudo electro-mechanical dissociation (P-EMD) with standard chest compressions leads to periods where the chest compressions and heart-beat are in phase and periods where the chest compression and heart-beat are out of phase. We hypothesized that synchronized chest compressions will improve hemodynamics relative to standardized chest compressions during P-EMD. Methods: Eight animals underwent surgical preparation and were exposed to hypoxia to induce P-EMD. The treatment period was divided into eight 45 sec epochs during which the P-EMD was left untreated or was treated with standard chest compressions or chest compressions synchronized to the R-wave in the ECG. For each epoch of CPR in each animal, we measured the rate of change in the hemodynamics over the last half of the epoch using linear regression. ANOVA modeling was used to compare changes in hemodynamics as a function of treatment. Results: The rate of change in coronary perfusion pressure (CPP), minimum right atrial pressure (RAPmin), and maximum right atrial pressure (RAPmax) was larger during synchronized compressions than during standard compressions or untreated P-EMD. The rate of change in AOPmin was larger during both treatments than during untreated P-EMD. Other differences in the rate of change were not detected between standard chest compressions and untreated P-EMD. Numerical results are shown in the table below. RAPmax decreased over time, while the other measures increased. Conclusions: Synchronized chest compressions improved several blood pressure metrics over time during P-EMD, while standardized chest compressions only improved AOPmin. While some of the changes are modest, they were sustained over 20 seconds, suggesting that continued delivery of synchronized chest compressions could result in clinically meaningful improvement in blood pressures. Table 1. ANOVA comparison of blood pressures as a function of treatment

Resuscitative effect of aortic balloon occlusion on traumatic cardiac arrest in swine

Objective To investigate the resuscitation effect of aortic balloon occlusion (ABO) on the traumatic cardiac arrest (TCA) in swine. Methods Twenty-seven male domestic swine weighing (32.7±3.8)kg were utilized. After 40% of estimated blood volume was removed within 20 minutes, the animals were subjected to 5 minutes of untreated ventricular fibrillation and then 5 minutes of cardiopulmonary resuscitation. Additionally, fluid resuscitation was initiated coincident with the beginning of cardiopulmonary resuscitation. The animals were randomly divided into model group (n=12) and ABO group (n=15). Once cardiopulmonary resuscitation was implemented, aortic balloon was concurrently inflated to stop the blood flow of descending thoracic aorta at the level of the diaphragm in the ABO group. In the model group, aortic balloon was placed in the same position without inflation. During cardiopulmonary resuscitation, the changes of coronary perfusion pressure (CPP), forehead's regional cerebral oxygen saturation (rSO2) and pressure of end-tidal CO2 (PETCO2) were continuously monitored, and the rate of return of spontaneous circulation (ROSC), duration of cardiopulmonary resuscitation, number of shocks and dose of epinephrine were recorded. At 5 minutes after successful resuscitation, the levels of arterial blood gas, lactate and jugular venous blood oxygen saturation (SjvO2) were measured. Results Compared with the model group, the values of CPP, rSO2 and PETCO2 during cardiopulmonary resuscitation were significantly increased in the ABO group [CPP: (33.5±5.6)mmHg vs. (23.1±5.2)mmHg at 1 minute, (35.3±6.0)mmHg vs. (26.8±7.4)mmHg at 2 minutes, (36.3±6.3)mmHg vs. (28.2±6.3)mmHg at 3 minutes, (40.1±7.1)mmHg vs. (30.5±6.2)mmHg at 4 minutes, (38.1±7.5)mmHg vs. (29.8±5.3)mmHg at 5 minutes; rSO2: (45.4±5.2)% vs. (39.2±5.1)% at 1 minute, (47.2±3.6)% vs. (42.0±6.4)% at 2 minutes, (47.7±3.0)% vs. (41.5±5.4)% at 3 minutes, (47.0±2.5)% vs. (42.1±5.9)% at 4 minutes, (47.1±2.0)% vs. (41.5±7.4)% at 5 minutes; PETCO2: (17.0±3.5)mmHg vs. (12.7±4.2)mmHg at 1 minute, (18.5±3.7)mmHg vs. (14.5±2.7)mmHg at 2 minutes, (20.7±5.3)mmHg vs. (15.5±3.2)mmHg at 3 minutes, (18.7±4.5)mmHg vs. (14.9±3.5)mmHg at 4 minutes, (18.2±3.2)mmHg vs. (14.5±4.2)mmHg at 5 minutes] (all P<0.05). The rate of ROSC was significantly higher in the ABO group than in the model group[100%(15/15) vs. 75%(9/12)] (P<0.05). Additionally, shorter duration of cardiopulmonary resuscitation, less number of shocks and lower doses of epinephrine were observed in the ABO group when compared with the model group[duration of cardiopulmonary resuscitation: 5(5, 5)minutes vs. 5(5, 12.5)minutes, number of shocks: 1(1, 1)times vs. 1(1, 4)times, dose of epinephrine: 0.62(0.62, 0.74)mg vs. 0.64(0.59, 2.59)mg] (all P<0.05). At 5 minutes after resuscitation, the level of arterial lactate was significantly decreased and the value of SjvO2 was significantly increased in the ABO group compared with the model group[Lactate: (9.6±0.8)mmol/L vs. (10.8±1.4)mmol/L; SjvO2: (50.0±8.6)% vs. (37.9±16.3)%] (both P<0.05). Conclusions In a swine model of TCA, ABO can increase cardiac and cerebral perfusion during cardiopulmonary resuscitation and improve the efficacy of cardiopulmonary resuscitation. It might provide a novel and effective method for the resuscitation of TCA in the clinical setting. Key words: Heart arrest; Cardiopulmonary resuscitation; Aortic balloon occlusion

Local metabolic hypothesis is not sufficient to explain coronary autoregulatory behavior.

The local metabolic hypothesis proposes that myocardial oxygen tension determines the degree of autoregulation by increasing the production of vasodilator metabolites as perfusion pressure is reduced. Thus, normal physiologic levels of coronary venous PO2, an index of myocardial oxygenation, are proposed to be required for effective autoregulation. The present study challenged this hypothesis through determination of coronary responses to changes in coronary perfusion pressure (CPP 140-40mmHg) in open-chest swine in the absence (n = 7) and presence of euvolemic hemodilution (~ 50% reduction in hematocrit), with (n = 5) and without (n = 6) infusion of dobutamine to augment MVO2. Coronary venous PO2 decreased over similar ranges (~ 28-15mmHg) as CPP was lowered from 140 to 40mmHg in each of the groups. However, coronary venous PO2 was not associated with changes in coronary blood flow (r = - 0.11; P = 0.29) or autoregulatory gain (r = - 0.29; P = 0.12). Coronary zero-flow pressure (Pzf) was measured in 20mmHg increments and determined to be directly related to vascular resistance (r = 0.71; P < 0.001). Further analysis demonstrated that changes in coronary blood flow remained minimal at Pzf > 20mmHg, but progressively increased as Pzf decreased below this threshold value (r = 0.68; P < 0.001). Coronary Pzf was also positively correlated with autoregulatory gain (r = 0.43; P = 0.001). These findings support that coronary autoregulatory behavior is predominantly dependent on an adequate degree of underlying vasomotor tone, independent of normal myocardial oxygen tension.

The Effects of Chronic Administration of Cisplatin on Oxidative Stress in the Isolated Rat Heart

AbstractTaken into consideration that molecular and cellular mechanisms involved in cardiotoxicity are still not clear the aim of this study was to compare the production of oxidative stress parameters in the isolated rat heart between animals chronically treated with cisplatin and saline. The hearts of male Wistar albino rats (n = 24, 12 per group, age 8 weeks, body mass 250±50 g) were excised and perfused according to the Langendorff technique at gradually increased coronary perfusion pressures (40-120 cm H2O). We followed the production of superoxide anion radicals, hydrogen peroxide, and nitrites and also index of lipid peroxidation during the changes of coronary perfusion pressure (CPP) (from 40 to 120 cm H2O) in coronary venous effluent. Modifications CPP were performed in order to determined if oxidative stress is involved in coronary endothelium response in conditions of hypoxia (lower than 60 cm H2O) and hyperoxia (higher than 80 cm H2O).Based on the results of this research we can conclude that with enhancement of CPP the values of oxidative stress statistically increased. However, this increment is more prominent in control group as a result of preserved endothelium and its more powerful response to hyperoxia. On the other hand, damaged endothelium of cisplatin-treated animals had weaker response to hyperoxia, and also lower antioxidant capacity.

The Effects of Chronic Administration of Cisplatin on Oxidative Stress in the Isolated Rat Heart

AbstractTaken into consideration that molecular and cellular mechanisms involved in cardiotoxicity are still not clear the aim of this study was to compare the production of oxidative stress parameters in the isolated rat heart between animals chronically treated with cisplatin and saline. Th e hearts of male Wistar albino rats (n = 24, 12 per group, age 8 weeks, body mass 250±50 g) were excised and perfused according to the Langendorff technique at gradually increased coronary perfusion pressures (40-120 cmH2O). We followed the production of superoxide anion radicals, hydrogen peroxide, and nitrites and also index of lipid peroxidation during the changes of coronary perfusion pressure (CPP) (from 40 to 120 cm H2O) in coronary venous effluent. Modifications CPP were performed in order to determined if oxidative stress is involved in coronary endothelium response in conditions of hypoxia (lower than 60 cm H2O) and hyperoxia (higher than 80 cm H2O). Based on the results of this research we can conclude that with enhancement of CPP the values of oxidative stress statistically increased. However, this increment is more prominent in control group as a result of preserved endothelium and its more powerful response to hyperoxia. On the other hand, damaged endothelium of cisplatin-treated animals had weaker response to hyperoxia, and also lower antioxidant capacity.

Posttraumatic Stress Disorder Disturbs Coronary Tone and Its Regulatory Mechanisms.

Posttraumatic stress disorder (PTSD) is associated with myocardial injury, but changes in coronary regulatory mechanisms in PTSD have not been investigated. This study evaluated the effect of PTSD-inducing stress on coronary tone and its regulation by nitric oxide (NO) and voltage-gated K+ channels. PTSD was induced by exposing rats to predator stress, 15min daily for 10days, followed by 14 stress-free days. Presence of PTSD was confirmed by the elevated plus-maze test. Coronary tone was evaluated from changes in coronary perfusion pressure of Langendorff isolated hearts. Predator stress induced significant decreases in coronary tone of isolated hearts and in blood pressure of intact rats. L-NAME, a non-selective NO synthase (NOS) inhibitor, but not S-MT, a selective iNOS inhibitor,and increased coronary tone of control rats. In PTSD rats, both L-NAME and S-MT increased coronary tone. Therefore, the stress-induced coronary vasodilation resulted from NO overproduction by both iNOS and eNOS. NOS induction was apparently due to systemic inflammation as evidenced by increased serum interleukin-1β and C-reactive protein in PTSD rats. Decreased corticosterone in PTSD rats may have contributed to inflammation and its effect on coronary tone. PTSD was also associated with voltage-gated K+ channel dysfunction, which would have also reduced coronary tone.

Computational simulation of passive leg-raising effects on hemodynamics during cardiopulmonary resuscitation

Background and objectiveThe passive leg-raising (PLR) maneuver has been used for patients with circulatory failure to improve hemodynamic responsiveness by increasing cardiac output, which should also be beneficial and may exert synergetic effects during cardiopulmonary resuscitation (CPR). However, the impact of the PLR maneuver on CPR remains unclear due to difficulties in monitoring cardiac output in real-time during CPR and a lack of clinical evidence. MethodsWe developed a computational model that couples hemodynamic behavior during standard CPR and the PLR maneuver, and simulated the model by applying different angles of leg raising from 0° to 90° and compression rates from 80/min to 160/min. ResultsThe simulation results showed that the PLR maneuver during CPR significantly improves cardiac output (CO), systemic perfusion pressure (SPP) and coronary perfusion pressure (CPP) by ∼40–65% particularly under the recommended range of compression rates between 100/min and 120/min with 45° of leg raise, compared to standard CPR. However, such effects start to wane with further leg lifts, indicating the existence of an optimal angle of leg raise for each person to achieve the best hemodynamic responses. ConclusionsWe developed a CPR-PLR model and demonstrated the effects of PLR on hemodynamics by investigating changes in CO, SPP, and CPP under different compression rates and angles of leg raising. Our computational model will facilitate study of PLR effects during CPR and the development of an advanced model combined with circulatory disorders, which will be a valuable asset for further studies.

Selective Alpha7 Nicotinic Receptor Agonist Increases Cardiac Function in Isolated Mouse Hearts by a Non-Nicotinic Mechanism

Selective alpha7 nicotinic receptor agonists, such as GTS-21, are known to have neuroprotective and anti-inflammatory actions, but the effect of these agents on the heart is not known. Therefore, we evaluated the actions of GTS-21 in isolated atria and isolated hearts from C57BL/6 mice. GTS-21 (1-100 μM) caused a concentration-dependent increase in amplitude of contractions and decrease in beating rate in isolated atria. Percent changes in rate and contractile force evoked by 30 μM GTS-21 were −14 ± 2 and +36 ± 11, respectively (n = 4). The onset of responses to GTS-21 was slower than would occur to acetylcholine and norepinephrine, and effects of GTS-21 were not blocked by atropine or atenolol. The impact of GTS-21 on left ventricular function was evaluated next in isolated hearts paced at 400 BPM. Treatment with 30 µM GTS-21 caused significant increases in contractile function: developed pressure (+30 ± 4%); peak systolic pressure (+16 ± 2%); dP/dtmax (+31 ± 6%). Diastolic pressure was also decreased (−60 ± 10%) while the rate of relaxation increased (-dP/dtmax, +36 ± 6%) with no sizable change in coronary perfusion pressure (p < 0.05 for all parameters, n = 4). Surprisingly, responses to GTS-21 were not affected by a selective alpha7 antagonist or the nonselective nicotinic antagonist mecamylamine, and there was no evidence of desensitization. Our data demonstrate that GTS enhances atrial and ventricular contractility and improves LV relaxation with a modest decrease in heart rate. GTS-21 cardiac actions occur by a mechanism that is independent of nicotinic receptors and autonomic nerves. The unique profile of cardiac effects for GTS-21 suggests its potential use in the setting of acute heart failure.

Ultrasound shear wave elasticity imaging quantifies coronary perfusion pressure effect on cardiac compliance.

Diastolic heart failure (DHF) is a major source of cardiac related morbidity and mortality in the world today. A major contributor to, or indicator of DHF is a change in cardiac compliance. Currently, there is no accepted clinical method to evaluate the compliance of cardiac tissue in diastolic dysfunction. Shear wave elasticity imaging (SWEI) is a novel ultrasound-based elastography technique that provides a measure of tissue stiffness. Coronary perfusion pressure affects cardiac stiffness during diastole; we sought to characterize the relationship between these two parameters using the SWEI technique. In this work, we demonstrate how changes in coronary perfusion pressure are reflected in a local SWEI measurement of stiffness during diastole. Eight Langendorff perfused isolated rabbit hearts were used in this study. Coronary perfusion pressure was changed in a randomized order (0-90 mmHg range) and SWEI measurements were recorded during diastole with each change. Coronary perfusion pressure and the SWEI measurement of stiffness had a positive linear correlation with the 95% confidence interval (CI) for the slope of 0.009-0.011 m/s/mmHg ( R(2) = 0.88 ). Furthermore, shear modulus was linearly correlated to the coronary perfusion pressure with the 95% CI of this slope of 0.035-0.042 kPa/mmHg ( R(2) = 0.83). In conclusion, diastolic SWEI measurements of stiffness can be used to characterize factors affecting cardiac compliance specifically the mechanical interaction (cross-talk) between perfusion pressure in the coronary vasculature and cardiac muscle. This relationship was found to be linear over the range of pressures tested.

Hemodynamic Effect of External Chest Compressions at the Lower End of the Sternum in Cardiac Arrest Patients

BackgroundLittle is known about the hemodynamic effects of chest compression at different positions on the sternum during cardiopulmonary resuscitation (CPR). ObjectivesThis study aimed to test whether external chest compression at the lower end of the sternum as an alternative position (alternative compression) results in superior hemodynamic effects compared to standard external chest compression (standard compression). MethodsWe enrolled 17 patients with non-traumatic cardiac arrest who failed to regain spontaneous circulation within 30 min after CPR initiation. Standard compression was begun when cardiac arrest was confirmed. Alternative compression was performed for 2 min if spontaneous circulation was not attained after 30 min of standard CPR. We compared hemodynamics and end-tidal CO2 pressure during the last 2 min of standard compression and during alternative compression. ResultsPeak arterial pressure during compression systole (114 ± 51 vs. 95 ± 42 mm Hg, p < 0.001) and end-tidal CO2 pressure (11.0 ± 6.7 vs. 9.6 ± 6.9 mm Hg, p < 0.05) were higher with alternative than standard compression, whereas arterial pressure during compression diastole, peak right atrial pressure, and coronary perfusion pressure did not differ between standard and alternative compression. ConclusionsCompared to standard compression, alternative compression results in a higher peak arterial pressure and end-tidal CO2 pressure, but no change in coronary perfusion pressure.

Contribution of Voltage‐Dependent Potassium &amp; Calcium Channels to Coronary Pressure‐Flow Autoregulation

The goal of this investigation was to test the hypothesis that voltage‐sensitive potassium (KV) and calcium (CaV1.2) channels contribute to coronary pressure‐flow autoregulation in vivo. This hypothesis was tested in open‐chest, anaesthetized Ossabaw swine during step changes in coronary perfusion pressure (CPP) from 140‐40 mmHg before/during inhibition of KV channels with 4AP (0.3 mM, ic) or CaV1.2 channels with diltiazem (10 μg/min, ic). 4AP significantly decreased vasodilatory responses to H2O2 (0.3 – 10 μg/min) and blood flow at CPPs = 140‐60 mmHg. This decrease in coronary flow was associated with diminished ventricular contractile function (dP/dT) and myocardial oxygen consumption. However, the overall sensitivity to changes in CPP from 120 to 60 mmHg (i.e. autoregulatory gain; Gc) was unaltered by 4‐AP administration (Gc = 0.35 ± 0.11 control vs. 0.39 ± 0.07 4‐AP). In contrast, diltiazem markedly increased coronary blood flow at CPPs &gt; 80 mmHg and decreased coronary autoregulatory gain (Gc = −0.21 ± 0.08) relative to control (P &lt; 0.01), with no effect on contractile function or oxygen consumption. Taken together, our findings demonstrate that: 1) KV channels tonically contribute to the control of vascular resistance over a wide range of CPPs; 2) CaV1.2 channels play a critical role in coronary pressure‐flow autoregulation.

Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-flow autoregulation

The mechanisms responsible for coronary pressure-flow autoregulation, a critical physiologic phenomenon that maintains coronary blood flow relatively constant in the presence of changes in perfusion pressure, remain poorly understood. This investigation tested the hypothesis that voltage-sensitive K(+) (K(V)) and Ca(2+) (Ca(V)1.2) channels play a critical role in coronary pressure-flow autoregulation in vivo. Experiments were performed in open-chest, anesthetized Ossabaw swine during step changes in coronary perfusion pressure (CPP) from 40 to 140 mmHg before and during inhibition of K(V) channels with 4-aminopyridine (4AP, 0.3 mM, ic) or Ca(V)1.2 channels with diltiazem (10 μg/min, ic). 4AP significantly decreased vasodilatory responses to H(2)O(2) (0.3-10 μM, ic) and coronary flow at CPPs = 60-140 mmHg. This decrease in coronary flow was associated with diminished ventricular contractile function (dP/dT) and myocardial oxygen consumption. However, the overall sensitivity to changes in CPP from 60 to 100 mmHg (i.e. autoregulatory gain; Gc) was unaltered by 4-AP administration (Gc = 0.46 ± 0.11 control vs. 0.46 ± 0.06 4-AP). In contrast, inhibition of Ca(V)1.2 channels progressively increased coronary blood flow at CPPs > 80 mmHg and substantially diminished coronary Gc to -0.20 ± 0.11 (P < 0.01), with no effect on contractile function or oxygen consumption. Taken together, these findings demonstrate that (1) K(V) channels tonically contribute to the control of microvascular resistance over a wide range of CPPs, but do not contribute to coronary responses to changes in pressure; (2) progressive activation of Ca(V)1.2 channels with increases in CPP represents a critical mechanism of coronary pressure-flow autoregulation.

Contribution of IKCa channels to the control of coronary blood flow

The purpose of this investigation was to elucidate the contribution of intermediate conductance calcium-activated potassium channels (IK(Ca)) to the regulation of coronary blood flow in vivo. We hypothesized that IK(Ca) channels modulate coronary arteriolar resistance at rest and contribute to vasomotor responses to changes in coronary perfusion pressure and/or in response to cardiac ischemia. Experiments were conducted in open-chest anesthetized dogs in the absence and presence of IK(Ca) channel inhibitor, TRAM-34 (1 μg/min, intracoronary), and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME) (150 μg/min, intracoronary). We found that administration of the potent SK(Ca) and IK(Ca) channel agonist NS309 dose-dependently increased coronary blood flow and that inhibition of IK(Ca) channels with TRAM-34 attenuated this response by ∼90%. The increase in coronary blood flow to NS309 was also decreased ∼100% by the inhibition of NO production with L-NAME. Multiple linear regression analysis demonstrated that TRAM-34 diminished the autoregulatory capability of the coronary circulation at coronary pressures ranging from 60 to 120 mmHg. However, inhibition of IK(Ca) channels did not affect coronary vasodilation in response to a transient 15 s coronary artery occlusion (i.e. reactive hyperemia). Our data reveal that IK(Ca) channels are functionally expressed in the coronary circulation and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IK(Ca) channels modestly contribute to changes in coronary vascular resistance in response to alterations in coronary perfusion pressure but do not contribute to the reactive hyperemic response following a brief coronary artery occlusion.

Contribution of IKCa Channels to the Control of Coronary Blood Flow

The purpose of this investigation was to determine the role of intermediate conductance calcium‐activated potassium channels (IKCa) in regulating coronary arteriolar resistance at rest, in response to changes in coronary perfusion pressure, and during cardiac ischemia. Experiments were conducted in open‐chest anesthetized dogs in the presence of IKCa channel inhibitor, TRAM‐34 (1 μg/min, ic), or the nitric oxide (NO) synthase inhibitor, L‐NAME (150 μg/min, ic). Administration of the SKCa and IKCa channel agonist NS309 dose‐dependently increased coronary blood flow and inhibition of IKCa channels with TRAM‐34 attenuated this response by ~ 90%. The increase in coronary blood flow with NS309 was also decreased ~100% by L‐NAME. In addition, TRAM‐34 diminished the autoregulatory capability of the coronary circulation at pressures ranging from 60 – 120 mmHg. However, inhibition of IKCa channels did not affect coronary reactive hyperemia. Our data reveal that IKCa channels are functionally expressed in the coronary vasculature and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IKCa channels modestly regulate vascular resistance in response to alterations in coronary perfusion pressure but do not modulate coronary vasodilation in response to cardiac ischemia. Support 10PRE4230035, HL092245

Characteristics of hemodynamics during closed chest cardiopulmonary resuscitation

Objective To study the hemodynamics during closed chest cardiopulmonary resuscitation (CCCPR) in dogs in order to unravel the mechanism. Method Twelve healthy mongrel dogs were selected to make animal model of ventricular fibrillation induced by electric shock on the chest wall. Closed-chest cardiopulmonary resuscitation (CCCPR) was initiated four minutes after ventricular fibrillation appeared according to American Heart Guidelines in 2005 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Rescue. After CPR for 2 minutes, 1mg epinephrine was injected intravenously. The central venous pressure (CVP), the aortic pressure (AOP)and the invasive electrocardiogram (ECG) were used to monitor continuously before ventricular fibrillation and the entire course of CPR. The coronary perfusion pressure (CPP) was calculated. The changes in aortic diastolic pressure (ADP) and CPP produced by chest compression or the injection of epinephrine were analyzed. The aortic pressure and the central venous pressure were recorded simultaneously during CPR. A chart was made and the CPP was calculated with the software Chart5Ch. The hemodynamic changes produced by the administration of epinephrine were studied. Data were analyzed with paired Student t test. P ＜ 0.05 was considered as a significant difference. Results Two kinds of hemodynamic effects of CPR were observed. In 8 dogs (8/12) , the aortic pressure changed synchronously with the CVP, and the CPP was almost zero, and in other 4 dogs (4/12), the aortic pressure increased and the CVP remained unchanged with presence of the CPP. After the administration of epinephrine, the AOP and the CPP increased significantly. The Aortic systolic pressure(ASP) increased from (66± 14) mmHg to(107 ± 28) mmHg, (P = 0. 001). The Aortic diastolic pressure (ADP) increased from (25 ±2.2) mmHg to(45 ± 13) mmHg (P =0.001). And the coronary perfusion pressure (CPP) increased from (2.8± 3.8) mmHg to (29 ± 13) mmHg (P ＜ 0.001). The 95 % confidential interval of the added value of the ASP,ADP and CPPwere (21.1-59.1), (10.2-28.3) and (16.7-35.7), respectively. Conclusions The thoracic pump mechanism is the primary role in the closed chest Cardiopulmonary resuscitation. Epinephrine can increase ADP and CPP and has the capability to break the balance between aortic pressure and central venous pressure, increasing the rate of successful cardiopulmonary resuscitation. Key words: Cardiopulmonary resuscitation; Closed chest; Hemodynamics; Epinephrine; Mechanism

Rescue of amitriptyline-intoxicated hearts with nanosized vesicles

Amitriptyline, one of the most prescribed antidepressants, is reported to claim a large number of human lives due to drug overdose related cardiac arrest. Although amitriptyline poisoning has long been recognized as a frequent and serious fatality in the medical field, few efforts have been made to devise methods for treating its toxicity. To address this issue, phospholipid-based nanosized vesicles (spherulites) were employed to reverse the cardiotoxicity induced by amitriptyline in an isolated heart perfusion model. The ability of spherulites to efficiently take up amitriptyline was first established in vitro in protein free and albumin-containing buffers. Vesicles bearing an internal pH of 3.0 or 7.4 were then infused into amitriptyline pre-intoxicated isolated rat hearts, and changes in coronary perfusion pressure (CPP), the first derivative of left ventricular pressure (dP/dt max) and heart rate were monitored. Control hearts received no vesicles. Based on the recoveries in CPP observed, the efficacies of the formulations were ranked as follows: control=pH 7.4-spherulites<pH 3.0-spherulites; whereas the ranking for the recoveries in heart rate was: control<pH 7.4-spherulites<pH 3.0-spherulites. The significantly faster and higher recoveries in pH 3.0- vs. 7.4-spherulite-treated hearts demonstrated the importance of pH-gradient formulation for efficient extraction of tissue-bound amitriptyline. These data suggest that spherulites have a protective effect against acute cardiovascular failure following intoxication with amitriptyline and possibly other cardiotoxic drugs. It appears that the beneficial effects derived from the formulation infusion involved restoration of both haemodynamic and metabolic oxygen demands on the heart.

Microcirculation during cardiac arrest and resuscitation

Direct observations of the microcirculation using orthogonal polarization spectral imaging have attracted attention and revealed that, especially in cardiogenic and distributive shock, there is discordance between the macrocirculation and the microcirculation. We evaluated serial changes and the effects of epinephrine on microcirculatory blood flow in the most severe form of circulatory failure, namely, cardiac arrest. : Controlled laboratory animal study. A total of 15 pigs were subjected to 5 mins of ventricular fibrillation and 5 mins of precordial compression before electrical defibrillation was attempted. In a subset, six animals received 1 mg of epinephrine after 1 min of precordial compression. Microcirculatory blood flow was visualized in the sublingual mucosa at baseline and 0.5, 1, and 5 mins of ventricular fibrillation, at 1 and 5 mins of precordial compression, and at 1 and 5 mins after return of spontaneous circulation. In addition, coronary perfusion pressure was recorded. Microcirculatory blood flow decreased dramatically in the 0.5 min after the onset of ventricular fibrillation. Precordial compression partially restored microcirculatory blood flow in each animal but to a significantly greater extent in animals that achieved return of spontaneous circulation. These changes were paralleled by similar changes in coronary perfusion pressure. Both variables were highly correlated. Administration of epinephrine resulted in a massive reduction of microcirculatory blood flow that lasted for >/=5 mins. In this model, microcirculatory blood flow was highly correlated with macrocirculatory hemodynamics, including coronary perfusion pressure in distinction with septic shock. Administration of epinephrine dramatically decreased microcirculatory blood flow.