Gravedad Específica

The ideal coronary vasodilator for measuring coronary flow reserve in man should induce maximum vasodilatation in a predictable manner, be short-acting to allow repeated measurement and should not alter systemic haemodynamics. The most frequently used drugs for measuring coronary flow reserve include papaverine, dipyridamole and adenosine.

4.2.1.1 Papaverine

Papaverine has become one of the most extensively used drugs for the assessment of coronary flow reserve. Papaverine is an opiate alkaloid, devoid of analgesic or narcotic

properties, which relaxes smooth muscle by the inhibition o f cyclic 3’,5’, AMP phosphodiesterase activity (Triner et al. 1970). Bolus injection of papaverine into the circumflex coronary artery o f the anaesthetised dog increased conductance (mean flow/systemic blood pressure) nearly four-fold, equivalent to the effect o f a 15 s occlusion of the coronary artery (Bookstein & Higgins 1976). Time to onset of maximal conductance after injection was 15+6 s. Coronary blood flow returned to 10% of basal flow after 110+37 s. In 1986 Wilson published data comparing papaverine, dipyridamole and meglumine diatrizoate for the assessment of coronary flow reserve in man (Wilson et al. 1986b). The increase in coronary blood flow velocity measured with an intracoronary Doppler flow probe was comparable with dipyridamole, and both were superior to meglumine diatrizoate. The onset o f action was rapid (16+1 s) and the duration o f hyperaemic flow was brief (49+10 s). Maximum dilatation was achieved with 8 mg papaverine in the right coronary artery and with 12 mg in the left coronary artery. Wilson concluded that papaverine was an ideal coronary vasodilator for studies in the human coronary circulation. Zijlstra studied the properties of papaverine using coronary sinus thermodilution and reached similar conclusions (Zijlstra et al. 1986).

The effects of papaverine on epicardial coronary artery dimensions must be considered if coronary flow reserve is measured with an intracoronary Doppler flow probe. Papaverine dilates normal and stenotic coronary arteries. Papaverine increases the cross-sectional area of a normal artery by up to 14% (Carlson et al. 1988) and the cross-sectional area of a stenosis increases approximately 18% (Zijlstra et al. 1988b). Coronary flow reserve will be underestimated using a Doppler flow probe unless changes in coronary artery size are determined, for example with quantitative angiography.

Intracoronary papaverine causes electrocardiographic changes, including transient ST segment depression, T wave inversion and QT^ prolongation. Ventricular arrhythmias have been documented following papaverine administration, but their occurrence is rare. Isolated cases o f ventricular tachycardia (Wilson & White 1986b & 1988b; Vrolix et al. 1991) and ventricular fibrillation (Bookstein & Higgins 1977) have been reported with papaverine. Possible predisposing factors include multiple administration, a prolonged QT^ interval on the resting electrocardiogram, and other factors which affect repolarisation, for example alkalosis and hypokalaemia (Wilson & White 1988b; Vrolix et ai. 1991). In a review o f 391 consecutive patients who received intracoronary papaverine, polymorphous ventricular tachycardia occured in 5 patients (1.3%) (Talman et al. 1990). In common with all isolated case reports, the arrhythmia was short-lasting and either reverted spontaneously or sinus rhythm was restored by electrical cardioversion.

Plasma K'*' and QT^ were determined in all patients prior to study and patients were excluded if values were outside the normal range. Patients were warned of the possibility of rhythm change with papaverine and a temporary pacing wire was positioned in the right ventricle as a precaution. Multiple injections of papaverine were avoided. No significant rhythm change occured in any of the patients studied, but ST/T wave changes and transient QT prolongation were frequently seen.

4.2.1.2 Adenosine

Adenosine is the final product of the stepwise dephosphorylation of ATP. Many different cell types produce adenosine, which has a half-life outside the cell of only a few seconds. Adenosine acts on P| purinoceptors which are located on a wide variety of cell types, and are subdivided into Aj and A2 subtypes. Stimulation o f Aj and A2

cardiac effects of adenosine are coronary vasodilatation and a negative chronotropic and dromotropic action on the conduction tissue (Drury & Szent-Gyorgi 1929). The potent vasodilator action led to the suggestion that adenosine is an important physiological mediator of coronary blood flow (Berne et al. 1963). The mechanism whereby adenosine mediates vasodilatation is not fully understood, but in human coronary arteries the A2 receptor is involved (Ramagopal et al. 1988).

Adenosine has been evaluated as a pharmacological agent for the assessment of coronary flow reserve in man. One of the first studies in man produced discouraging results. Zijlstra compared intracoronary adenosine and papaverine in 12 patients before and/or after PTCA using a Doppler tip balloon catheter (Zijlstra et al. 1988c). The increase in coronary blood flow was similar with both drugs but the dose of adenosine was extremely variable, ranging from 0.05 mg to 0.80 mg. Significant bradyarrythmias were induced in 3 patients. Subsequent studies produced different results. In normal coronary arteries, 16 ^g boluses o f adenosine in the left coronary artery and 12 fig boluses in the right coronary artery induced coronary hyperaemia similar to that caused by papaverine (Wilson et al. 1990). The onset of maximum hyperaemia was rapid (11-12 s) and return to baseline flow occurred within approximately 60 s. Intracoronary adenosine induced a small and brief fall in systemic blood pressure with no significant change in heart rate. No rhythm change was observed with intracoronary adenosine but transient atrio-ventricular block developed in some patients during intravenous infusions of adenosine. The discrepancies between these two studies probably relate to the different patient populations studied. Intravenous infusion of adenosine is a promising method for assessing coronary flow reserve (Kern et al. 1991; Rossen et al. 1991).

4.2.1.3 Dipyridamole

Dipyridamole is used extensively in the evaluation o f patients with suspected or known coronary artery disease. Dipyridamole increases interstitial levels o f adenosine by inhibiting the cellular reuptake of adenosine and metabolism by adenosine deaminase (Klabunde 1983). The action of dipyridamole is competitively antagonised by aminophylline and other theophylline derivatives (Alfonso 1970). The standard dose of dipyridamole is 0.14 mg.kg"^.min”^ given as a slow intravenous injection (Gould 1978). Because maximum vasodilatation is not always obtained at this dose, some investigators recommend high-dose dipyridamole (0.84 mg.kg”^.min"^ total dose given over 10 min) (Picano et al. 1986). In a review of 3,911 patients who received low-dose dipyridamole, the most frequently reported side-effects were chest pain, headache, dizziness, ST/T changes on the electrocardiogram and ventricular extrasystoles (Ranhosky et ai. 1990). There were 2 non-fatal and 2 fatal myocardial infarctions; 3 of these patients had a history of unstable angina. Data on 10,451 high-dose dipyridamole-echocardiography tests performed on patients with known or suspected coronary artery disease indicate that the safety profile is similar to the low-dose test (Picano et al. 1992).

Papaverine was used for the assessment of coronary flow reserve in all patients reported in this thesis because of its favourable pharmacokinetic profile and the extensive experience which has been documented with the drug. The role of adenosine is promising and it was used in patients described in chapter 8. The long duration of action of dipyridamole is a limiting factor which prevents repeated evaluation of coronary flow reserve.

4.2.2 Assessment of endothelium-dependent dilatation