Isabelle Vergroesen

Oxygen and coronary vascular resistance during autoregulation and metabolic vasodilation in the dog

The hypothesis that tissue oxygen tension controls coronary vascular resistance during changes in perfusion pressure and oxygen consumption was expressed in a simplified mathematical form capable of making quantitative predictions. The predictive value of this formulation of the hypothesis was tested in experiments on anaesthetized mongrel dogs subjected to constant‐pressure perfusion of the left main coronary artery, with measurements of coronary blood flow and arterio‐venous oxygen content differences. Coronary venous oxygen content was used as an index of tissue oxygenation. The responses of coronary blood flow and arterio‐venous oxygen content difference, made over a range of perfusion pressures (which caused autoregulation) and heart rates (which caused metabolic regulation) were predicted qualitatively by the model. Coronary vascular conductance was positively related to metabolic rate only during metabolic regulation (heart rate changes); during autoregulation the relationship between these two variables was inverse. Coronary vascular conductance and resistance values taken from both interventions (both perfusion pressure and heart rate variations) were closely related to coronary venous oxygen content and calculated PO2. These findings suggest that further examination of oxygen tension, as the controller of the coronary vascular bed under physiological conditions should be considered.

Prolonged diastolic time fraction protects myocardial perfusion when coronary blood flow is reduced

BACKGROUND Because coronary blood flow is impeded during systole, the duration of diastole is an important determinant of myocardial perfusion. The aim of this study was to show that coronary flow modulates the duration of diastole at constant heart rate. METHODS AND RESULTS In anesthetized, open-chest dogs, diastolic time fraction (DTF) increased significantly when coronary flow was reduced by lowering perfusion pressure from 100 to 70, 55, and 40 mm Hg. On average, DTF increased from 0.47+/-0.04 to 0.55+/-0.03 after a pressure step from 100 to 40 mm Hg in control, from 0.42+/-0.04 to 0.47+/-0.04 after administration of adenosine, and from 0.46+/-0.07 to 0.55+/-0.06 after L-NMMA (mean+/-SD, 6 dogs for control and adenosine, 4 dogs for L-NMMA, all P<0.05). Flow normalized to its value at full dilation and pressure of 90 mm Hg (375+/-25 mL/min) increased during the period of reduced pressure at 40 mm Hg; control, from 0.005+/-63 (2 seconds after pressure step) to 0.09+/-0.06 (15 seconds after pressure step); with adenosine, from 0.19+/-0.06 to 0. 22+/-0.06; and with L-NMMA, from 0.013+/-0.007 to 0.12+/-0.02 (all P<0.05). The increase in DTF at low pressure may be explained by a decrease in interstitial volume at low pressure, which either decreases the preload of the myocytes or reduces the buffer capacity for ions determining repolarization, thereby causing an earlier onset of relaxation. CONCLUSIONS Because the largest increase in DTF occurs at pressures below the autoregulatory range when blood flow to the subendocardium is closely related to DTF, modulation of DTF by coronary blood flow can provide an important regulatory mechanism to match supply and demand of the myocardium when vasodilatory reserve is exhausted.

Antihypertensive and anti-ischemic effects of nicardipine and nitroprusside in patients undergoing coronary artery bypass grafting

The efficacy of nicardipine vs nitroprusside in controlling hypertension after sternotomy was compared in 120 patients undergoing coronary artery bypass grafting and anesthetized with fentanyl (100 micrograms/kg). All had good left ventricular function and had been receiving long term oral beta-blocking therapy. Patients were randomly allocated to 1 of 3 groups: group C, the control (n = 40), received no vasodilator; group N (n = 40) received intravenous nicardipine at an initial rate of 3 micrograms/kg/min; and group S (n = 40) received intravenous nitroprusside at an initial rate of 1 microgram/kg/min. Vasodilator infusion was begun before surgery and infusion rates were adjusted to maintain systolic blood pressure between 80 and 120% of postintubation (baseline) values. Additional measurements were obtained before incision and after sternotomy. In groups N and S, arterial blood pressure was effectively controlled in all patients. Before the incision, pulmonary artery pressure decreased in group S and systemic vascular resistance decreased in groups N and S. After sternotomy, mean arterial pressure, heart rate, pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index and rate-pressure product increased in group C. At this time, pulmonary artery pressure returned to baseline values in group S. In groups N and S, heart rate, cardiac index and rate-pressure product increased, but, compared with baseline values, systemic vascular resistance remained low after sternotomy. Ischemic changes were seen in the electrocardiogram in 11 patients (28%) in group C, 10 patients (25%) in group S and 4 patients (10%) in group N. The concentration of creatine phosphokinase MB was not significantly different in the first 24 postoperative hours in any group.

Dynamics of coronary adjustment to a change in heart rate in the anaesthetized goat.

1. We have previously shown that steady‐state coronary flow during auto‐regulation and metabolic rate changes is predicted by a mathematically expressed theory which assigns control of coronary vascular resistance to tissue PO2. Our present purpose was to test the applicability of this theory to the non‐steady state as exemplified by a sudden step change in heart rate. 2. The theory predicted that the response time of change of resistance in these circumstances would be slower with constant‐flow perfusion of the coronary bed than with constant‐pressure perfusion, and that with constant‐pressure perfusion only, the rate of adaption of resistance would be dependent on the level of pressure used. 3. These predictions were tested in open‐chest goats with cannulation of the left main coronary artery and perfusion with alternately constant pressure or constant flow. Sudden step changes in heart rate were induced by pacing to induce rapid transients in myocardial metabolic rate. 4. The half‐time of subsequent change in perfusion pressure‐flow ratio, which in the dynamical state is not equal to resistance, was 15.7 +/‐ 0.4 s (mean +/‐ S.E.M.), which was statistically shorter than for constant flow (22.2 +/‐ 0.5 s, P less than 0.001). 5. The half‐time of subsequent change in perfusion pressure‐flow ratio with constant‐pressure perfusion was 14.4 +/‐ 0.6 s at low pressure and 17.0 +/‐ 0.6 s at high pressure (P less than 0.001). 6. The results differed from those predicted by the theory, in that the changes described above were preceded by a rapid (5 s) step change in pressure‐flow ratio, up with an increase in heart rate and down with a decrease in heart rate. We postulated that this was a mechanical effect due to greater compression of the coronary microvasculature with more frequent contractions. 7. To test this hypothesis, we measured changes in coronary blood volume by integrating the difference between arterial inflow and venous outflow. These experiments showed a decrease in coronary blood volume with heart rate increase and vice versa. 8. Abolition of autoregulation and metabolic regulation was achieved with maximum vasodilatation of the coronary bed with adenosine. A sudden switch in heart rate then produced the initial step change in pressure‐flow ratio, but not the subsequent adaptation over 13‐25 s. This confirmed that the former effect is attributable to a passive mechanical mechanism.

The efficacy of nicardipine and nitroprusside in preventing poststernotomy hypertension

The efficacy of nicardipine and nitroprusside in preventing poststernotomy hypertension was compared in two groups of 45 patients undergoing coronary artery surgery. Patients were anesthetized with fentanyl, 100 micrograms/kg, and oxygen. Group N received nicardipine at an initial rate of 3 micrograms/kg/min. Group S received sodium nitroprusside at an initial rate of 1 microgram/kg/min. The vasodilators were started before surgery, and infusion rates were adjusted to maintain systolic blood pressure between 80% and 120% of postintubation (baseline) values. Additional measurements were obtained before incision and after sternotomy. In both groups, arterial blood pressure could be controlled effectively in all patients. In group S, pulmonary artery pressure (PAP) decreased before incision. At this time, systemic vascular resistance (SVR) decreased in both groups. After sternotomy, PAP returned to baseline values in group S. In both groups, heart rate, rate-pressure product, and cardiac index increased, while SVR remained decreased. In the period from induction of anesthesia to the start of cardiopulmonary bypass, the incidence of myocardial ischemia was greater (P less than 0.01) in group S (24%) than in group N (9%). Between the groups, the concentration of creatine phosphokinase MB was not significantly different in the first 24 hours postoperatively. In conclusion, it was shown that nicardipine may be a suitable alternative to nitroprusside for the prevention of poststernotomy hypertension and myocardial ischemia in patients undergoing coronary artery surgery.

Left ventricular pressure transmission to myocardial lymph vessels is different during systole and diastole.

In six open-thorax-anaesthetized dogs with paced hearts and a retrogradely cannulated epicardial lymph vessel, the sensitivity of myocardial lymph pressure to left ventricular pressure during systole and during diastole was determined. The lymph vessels were cannulated using PE-90 tubing, and lymph pressure was measured by connecting the cannula to a microtip pressure transducer. To obtain the systolic sensitivity, left ventricular pressure was changed by clamping the descending aorta, which caused left ventricular pressure to increase. The diastolic sensitivity was obtained from natural variation to left ventricular pressure caused by atrial contractions during induced long diastoles. The mean ratio of the pulse in lymph pressure to the pulse in left ventricular pressure was determined: systole: 0.069±0.013, n=213, diastole: 0.76±0.16, n=249 and, if possible, linear regression analysis between lymph and left ventricular pressure was performed. The systolic regression coefficients could be determined in six dogs and the diastolic coefficients in three dogs. During long diastoles lymph pressure variations are on average 76 per cent of those in the left ventricle. However, during systole, the sensitivity of lymph pressure to left ventricular pressure is more than ten times lower. It is not unlikely that the structural embedment of lymph vessels within the myocardium is such that volume variations by cardiac contraction are limited.

A critical appraisal of the rate pressure product as index of myocardial oxygen consumption for the study of metabolic coronary flow regulation.

For the assessment of metabolic coronary vasodilatation, changes in systolic rate pressure product (RPP) are frequently used to estimate the pacing- or exercise induced changes in myocardial oxygen consumption (MVO2). The present study was designed to test whether this is justified in patients with coronary artery disease. To study the relation between RPP and changes in MVO2 under different conditions, we used data from 21 patients who participated in two previous studies investigating the effect of nitroglycerin (NTG) and anaesthesia on metabolic coronary flow regulation. At control, during administration of NTG 1 microg/kg/min (n=11), and during anaesthesia (n=10), coronary sinus blood flow, MVO2 and RPP were measured at sinus rhythm and during atrial pacing (30 bpm above sinus rate) and the relation between the percentage increase in RPP (delta%RPP) and MVO2 delta%MVO2) was analysed, using standard linear regression analysis. Although a significant relation between delta%MVO2 and delta%RPP was found at control and during anaesthesia, prediction intervals were very wide and only 40% and 60% of the variation in delta%MVO2, respectively, could be explained by the variation in delta%RPP. During administration of NTG 1 microg/kg/min no significant relation was found between delta%MVO2 and delta%RPP. Thus, for the study of metabolic coronary flow regulation, pacing induced changes in MVO2 cannot be predicted accurately from changes in RPP.

Chronic cardiac denervation affects the speed of coronary vascular regulation

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

Myocardial oxygen supply:demand ratio as reference for coronary vasodilatory drug effects in humans.

OBJECTIVE: Introduction and measurement of human myocardial oxygen supply:demand ratio as a reference for quantification of coronary microvascular vasodilating drug effects in clinical studies. Myocardial oxygen consumption is the major determinant of coronary blood flow; therefore, the true vasodilating properties of coronary vasodilating drugs that may have an effect on oxygen consumption cannot be correctly assessed from blood flow changes alone. DESIGN: Prospective, controlled trial. SETTING: Academic hospital. PATIENTS: 12 patients with multivessel coronary artery disease (CAD) undergoing coronary artery bypass grafting. INTERVENTIONS: Cardiac pacing at 30 beats/min above sinus rhythm in awake and anaesthetised patients (fentanyl/pancuronium bromide). MAIN OUTCOME MEASURES: Myocardial oxygen supply, defined as coronary sinus blood flow multiplied by arterial oxygen content; myocardial oxygen demand, defined as coronary sinus blood flow multiplied by arteriovenous oxygen content difference. The change in oxygen demand induced by pacing was related to the change in myocardial oxygen supply in awake and anaesthetised patients. This myocardial oxygen supply:demand ratio determined in the reference study was compared with that induced by intravenous and intracoronary drugs (nifedipine, felodipine, urapidil, and sodium nitroprusside) in two pharmacological studies: patients with CAD undergoing cardiac surgery (45 treated with sodium nitroprusside, 27 with nifedipine, and 27 with urapidil to manage arterial blood pressure); and patients with unstable angina (and a similar degree of CAD) undergoing cardiac catheterisation for diagnostic purposes (10 treated with intracoronary nifedipine and 10 with intracoronary felodipine). RESULTS: When awake, the ratio of pacing induced oxygen supply:demand changes in the 12 reference study patients was 1.50 (95% confidence intervals (CI), 1.41-1.58), similar to the 1.45 (1.35-1.56) measured in the same patients after induction of anaesthesia. Anaesthesia per se did not increase coronary oxygen supply above the expected increase related to demand changes. The only significant change in the oxygen supply:demand ratio was induced by intracoronary bolus administration of nifedipine and felodipine (10.6 (SE 1.9) and 13.9 (1.9) ml/min, respectively, above the demand related supply). CONCLUSIONS: Quantification of coronary vasoactive properties in relation to the physiological reference ratio between myocardial oxygen supply and demand may be a powerful tool to differentiate between true and apparent coronary vasoactive drugs.

Rate of coronary flow adaptation in response to changes in heart rate before and during anesthesia for coronary artery surgery

Background The rate of adaptation of coronary blood flow in response to stepwise changes in heart rate (HR) has been extensively studied in dogs and goats to improve our understanding of the dynamics of coronary regulation processes and their pathophysiology and to obtain time constants for mathematical modeling of the coronary regulation. However, little is known about the dynamic characteristics of coronary flow adaptation in humans. In patients undergoing coronary artery surgery, we investigated the rate of coronary adaptation in response to stepwise changes in HR, in the awake and anesthetized states. Methods In 11 patients with stable coronary artery disease, arterial blood pressure, right atrial pressure, and coronary sinus blood flow, measured by continuous thermodilution, were calculated per beat. The ratio of beat-averaged arterial blood pressure minus right atrial pressure and coronary sinus blood flow was calculated to obtain an index of coronary resistance. The rate of change of coronary resistance index was quantified by t50, defined as the time required to establish 50% of the total change in coronary resistance index. Responses of coronary resistance index after HR changes, before and after induction of anesthesia, were compared. The anesthesia technique consisted of 100 micro gram *symbol* kg sup -1 fentanyl and 0.1 mg *symbol* kg sup -1 pancuronium bromide in combination with oxygen in air ventilation (FIO2 = 0.5). Results In the awake situation, t50 values of the dilating and constricting responses, induced by an increase and a decrease in HR were 5.0+/-2.1 (SD) s (range 2.6-9.0 s) and 5.7+/-1.2 s (range 4.1-7.8 s), respectively. During fentanyl/pancuronium anesthesia, the rate of coronary flow adaptation was significantly slower, with t50 values of 10.2+/-2.1 s (range 7.7-13.1 s) after an HR step-up and 9.8+/-2.1 s (range 6.6-13.2 s) after an HR step-down. Compared to the awake situation, arterial blood pressure was significantly reduced during anesthesia, but coronary vascular resistance remained unchanged. This implies that the steady-state static regulation of coronary blood flow had not changed. Conclusions These preliminary data suggest that, in patients with coronary artery disease, the rate of change in coronary vascular resistance in response to pacing-induced changes in HR is mitigated by fentanyl/pancuronium anesthesia during positive pressure ventilation. A further qualification of our findings in a larger number of patients is warranted.