Jasper E. Kal

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.

A randomized multicenter double-blind comparison of urapidil and ketanserin in hypertensive patients after coronary artery surgery☆

OBJECTIVES To compare the hemodynamic responses, safety, and efficacy of urapidil and ketanserin in hypertensive patients after coronary artery surgery. DESIGN Randomized double-blind study. SETTING Multi-institutional. PARTICIPANTS One hundred twenty-two patients undergoing elective coronary artery surgery. INTERVENTIONS When hypertension (defined as mean arterial pressure > 85 mmHg) developed within the first 2 hours after arrival in the intensive care unit, patients received urapidil (n = 62) or ketanserin (n = 60) to reach a mean arterial pressure between 65 and 75 mmHg. Urapidil was administered by repeated bolus injections (25 to 125 mg) followed by a continuous infusion of maximally 50 micrograms/kg/min. Ketanserin was administered by repeated bolus injections (10 to 50 mg) followed by a continuous infusion of maximally 4.0 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS A complete hemodynamic profile was determined at baseline and at 30 and 60 minutes after start of study medication. In the urapidil group, mean arterial pressure (+/-SD) decreased significantly from 100.6 +/- 12.4 mmHg at baseline to 74.6 +/- 12.1 mmHg at 30 minutes and 73.5 +/- 13.8 mmHg at 60 minutes. In the ketanserin group, mean arterial pressure decreased significantly from 98.7 +/- 10.7 mmHg at baseline to 83.5 +/- 16.8 mmHg at 30 minutes and 83.1 +/- 15.3 mmHg at 60 minutes. Between the groups, there was a significant difference in the degree of lowering mean arterial pressure at 30 and 60 minutes. Heart rate increased significantly by 5.8 +/- 12.7 (30 minutes) and 8.6 +/- 16.5 (60 minutes) beats/min in the ketanserin group. In the urapidil group, no changes in heart rate occurred. Cardiac output increased to the same extent (0.7 L/min) in both groups. Within and between the groups, there were no relevant changes in pulmonary filling pressures. The number of patients not responding adequately to the study medication (mean arterial pressure > 85 mmHg after 30 minutes despite the maximum doses of study medication) was comparable in both groups (9 [U] v 13 [K]). Adverse events attributable to the study medication occurred to a similar degree in both groups. In the patients treated with urapidil, a significantly higher incidence (32.3%) of hypotension (mean arterial pressure < or = 65 mmHg for more than 10 minutes) occurred after 60 minutes of continuous infusion. CONCLUSIONS In contrast to ketanserin, urapidil did not increase heart rate. Urapidil was more effective in lowering arterial blood pressure than ketanserin. However, one third of the patients treated with urapidil developed hypotension after 60 minutes of continuous infusion.

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.

The effect of nitroglycerin on pacing-induced changes in myocardial oxygen consumption and metabolic coronary vasodilation in patients with coronary artery disease.

UNLABELLED In the present study, we assessed the potential effect of nitroglycerin IV (NTG), a donor of exogenous nitric oxide, on metabolic coronary flow control in patients with coronary artery disease. In 12 patients scheduled for coronary artery surgery, arterial blood pressure, pulmonary capillary wedge pressure, coronary sinus blood flow (continuous thermodilution), myocardial oxygen supply (DVO2), and myocardial oxygen consumption (MVO2) were measured at sinus rhythm and in response to atrial pacing at 30 bpm greater than baseline sinus rate. These measurements were repeated during infusion of NTG 1 and 2 microg x kg(-1) x min(-1). At control, in the absence of NTG, MVO2 increased from 13.7 +/- 3.4 mL O2/min during sinus rhythm to 19.3 +/- 5.5 mL O2/min during pacing. NTG 1 and 2 microg x kg(-1) x min(-1) blunted the pacing-induced increase in MVO2 dose-dependently. During NTG 1 microg x kg(-1) x min(-1), MVO2 increased from 12.9 +/- 3.3 mL O2/min at sinus rhythm to 17.3 +/- 4.7 mL O2/min during pacing (P = 0.01 versus control pacing); during NTG 2 microg x kg(-1) x min(-1), MVO2 increased from 13.4 +/- 3.3 mL O2/min to 15.9 +/- 3.7 mL O2/min (P = 0.008 versus control pacing). However, the pacing-induced increase in DVO2 per mL O2/min increase in MVO2 (delta DVO2/delta MVO2), was significantly greater during the infusion of NTG 2 microg x kg(-1) x min(-1) (1.85 +/- 0.56; P = 0.023) compared with control (1.51 +/- 0.22). This was associated with an increase in coronary sinus hemoglobin oxygen saturation (30% +/- 5% at control pacing and 34% +/- 6% during pacing with NTG 2 microg x kg(-1) x min(-1); P = 0.018), which indicates that during the infusion of NTG, there was more metabolic coronary vasodilation than achievable solely on the basis of the metabolic stimulus. IMPLICATIONS Our findings suggest that nitroglycerin, a donor of exogenous nitric oxide, reduces pacing-induced increases in myocardial oxygen consumption and enhances metabolic coronary vasodilation in patients with coronary artery disease, in whom endogenous nitric oxide activity may be reduced.

Intracoronary-administered urapidil does not influence myocardial contractility, metabolic activity, or coronary sinus blood flow in humans

OBJECTIVE To compare the acute effect of intracoronary administration of urapidil and saline on myocardial contractility and metabolic activity. DESIGN Prospective, controlled, open-label study. SETTING University teaching hospital. PARTICIPANTS AND INTERVENTIONS Eight patients with stable coronary artery disease (CAD) undergoing elective percutaneous transluminal coronary angioplasty (PTCA) received normal saline followed by urapidil, 4 mg, injected directly into the left main coronary artery. MEASUREMENTS AND MAIN RESULTS Because local intracoronary administration is a non-steady-state condition, an in vitro model was used before the clinical experiments to establish the kinetic effects of acute administration of urapidil. The clinical experiments were performed in eight patients with CAD after PTCA. Measurements included a complete hemodynamic profile, coronary sinus blood flow (continuous thermodilution), left ventricular (LV) peak (+) dP/dt, LV peak (-) dP/dt, LV dP/dt/P(D)40, and LV end-diastolic pressures. Arterial and coronary venous blood samples were also obtained for the calculation of myocardial oxygen consumption. Baseline measurements I were first obtained, followed by intracoronary injection of 2 mL of saline. Additional measurements were obtained 1, 5, and 10 minutes after administration of saline. After a resting period (15 minutes), baseline measurements II, and intracoronary injection of urapidil, 4 mg (dissolved in 2 mL saline), additional measurements were obtained 1, 5, and 10 minutes later. Heart rate decreased 2.7+/-3.5 beats/min after injection of saline, whereas heart rate increased 2.0+/-1.8 beats/min after intracoronary urapidil, resulting in a significant difference in treatment effect (p = 0.003). There were no additional differences in treatment effect for any of the other measured or calculated parameters reflecting systemic hemodynamics, LV contractility, coronary dynamics, and myocardial metabolic activity. CONCLUSION The results suggest that intracoronary bolus administration of preservative-free urapidil, 4 mg, is not associated with any detectable effect on myocardial contractility or coronary smooth muscle in awake nonsurgical patients with CAD, after PTCA.

Calcium channel blockade with felodipine does not affect metabolic coronary vasodilation in patients with coronary artery disease.

The effect of calcium channel blockers may affect the feedback mechanism between myocardial metabolic activity and coronary blood flow. To test this hypothesis the effect of calcium channel blockade on metabolic coronary flow regulation was studied. In 10 patients with stable coronary artery disease, coronary sinus blood flow and myocardial oxygen supply and consumption (MV o 2 ) were measured both at sinus rhythm and during atrial pacing (30 beats/min above sinus rate), at control and during infusion of felodipine, a vasoselective dihydropyridine. The myocardial oxygen supply-consumption ratio at control (i.e., the slope of the regression line characterizing normal metabolic flow regulation) was 1.58 (95% CI, 1.38–1.80). Following infusion of felodipine, systemic and coronary vascular resistance during sinus rhythm decreased by 20 ± 11% and 23 ± 15%, respectively, and coronary venous oxygen saturation increased from 36 ± 6% at control to 42 ± 7% (p = 0.047) during infusion of felodipine. The myocardial oxygen supply-consumption ratio, characterizing metabolic flow regulation during felodipine, was 1.52 (95% CI, 1.26–1.78) and thus not different from control. Metabolic coronary flow regulation was not affected by administration of felodipine, although the setpoint of this regulation mechanism might have been offset by the initial drug-induced coronary vasodilation, which persisted during pacing.