Effects of Nitroprusside and Nitroglycerin on Coronary Blood Flow in Stenotic Arteries
Study in Patients with Single-Vessel Coronary Artery Disease
ABSTRACT: Objectives. To assess the effect of intravenous sodium nitroprusside and nitroglycerin on coronary blood flow distal to a severe coronary artery stenosis. Methods. Parameters of coronary arteries and coronary blood flow were measured distally to the stenosis during nitroprusside and nitroglycerin infusions in a dose producing a 25% decrease in mean arterial blood pressure in patients with single-vessel coronary artery disease. Results. Twenty patients (19 male, mean age 54.25 ± 9.72 years), with a 52–90% diameter reduction of the left anterior descending (LAD) artery were included in this study. Compared to baseline, only nitroglycerin produced a significant increase in the minimal lumen diameter of 18.02 ± 4.26% and minimal lumen area of 42.69 ± 10.18%. Both medications increased the distal vessel diameter. Nitroglycerin also produced a significant increase in the reference segment diameter. Despite the substantial pressure drop, there was no decrease in coronary blood flow (at rest or during hyperemia produced by intracoronary adenosine) or coronary flow reserve with both drugs. Nitroglycerin increased the hyperemic diastolic/systolic velocity ratio by 21.57 ± 8.97% (p < 0.05). Compared to baseline, there were significant reductions in the total and minimal coronary vessel resistance indices for both nitroprusside and nitroglycerin. Conclusion. In patients with a severe single coronary atherosclerotic lesion, intravenous infusion of nitroprusside and nitroglycerin in a dose sufficient to produce a substantial drop in mean arterial pressure does not lead to any decrease in coronary blood flow or coronary flow reserve.
J INVASIVE CARDIOL 2008;20:391–395
Key words: coronary artery disease; coronary blood flow;
coronary flow reserve
The effect of various medications on the coronary circulation is complex and not fully understood. Commonly-used vasoactive agents such as nitrates, calcium antagonists, angiotensin-converting enzyme inhibitors and sodium nitroprusside (NTP) act directly on the epicardial and small (resistant) arteries and arterioles, and indirectly by changing heart rate, cardiac preload and afterload and myocardial contractility as well.1–7 There are substantial differences in their effects on coronary hemodynamics depending on their route of administration — intravenous (IV) or intracoronary (IC). Recently, equivalent hyperemic responses of IC NTP to IC adenosine in patients with normal anterior descending arteries were reported.8 Our group has demonstrated a different effect of three medications (clonidine, NTP and nitroglycerin [NTG]) on coronary flow reserve (CFR) in normal coronary arteries.9 It is not clear how these medications administered intravenously affect coronary blood flow (CBF) and CFR in a region distal to a severe atherosclerotic lesion. The purpose of this study was to assess the effect of two commonly-used medications — NTP and NTG on CBF and CFR in stenotic anterior descending arteries.
Materials and Methods
Patient selection. Twenty patients (19 male, mean age 54.25 ± 9.72 years, range 34–72 years) were prospectively included in the study according to the following criteria: evidence of coronary artery disease based on medical history and/or noninvasive tests (electrocardiography, echocardiography, exercise stress test, 201 thalium scintigraphy); a ≥ 50% diameter stenosis of the left anterior descending artery (LAD) estimated by quantitative coronary angiography (QCA); and a distal segment of the artery free of disease and suitable for Doppler guidewire positioning and measurements. The mean diameter stenosis of the LAD was 71.4 ± 8.7% (range 52–90%).
The exclusion criteria were: systolic arterial pressure < 100 mmHg; hemoglobin < 110 g/l; clearly defined collateral filling of the artery; acute or subacute (< 4 weeks) myocardial infarction; left ventricular ejection fraction < 30%; significant valvular heart disease and high-grade atrioventricular block.
The investigation conforms to the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all patients and the study protocol was approved by the Ethics Committees of our hospitals.
Study protocol. After diagnostic angiography, a guiding catheter without side holes was introduced in the ostium of left coronary artery. Systolic (SABP), diastolic (DABP) and mean arterial (MABP) blood pressures were continuously monitored. A bipolar pacing electrode was introduced through the right femoral vein and positioned in the right atrium near the sinus node. After stabilizing in that position, overdrive pacing started with a rate of 10 beats per minute (bpm) higher than the patient’s basal rate and was maintained until the end of the study (Figure 1). A Doppler-tipped guidewire (FloWire®, Volcano Corp., San Diego, California) was placed at the distal segment of the LAD at least 5 mm distally to the stenosis and blood flow velocity was recorded at baseline conditions. After that, NTP was infused intravenously in increasing doses until the MABP stabilized about 25% below the baseline level. The infusion was maintained unchanged during the assessment of blood flow velocity and coronary flow velocity reserve (CFVR). At this point, a second coronary angiography was performed. After discontinuation of NTP infusion and blood pressure returned to basal values, IV infusion of NTG was started. NTG was infused at an incremental dose to produce the same degree of MABP decrease as the NTP infusion. The same measurements, as well as coronary angiography, were performed again.
Intracoronary Doppler measurements. Intracoronary flow velocity measurements were performed using the FloWire/FloMap system. The following parameters were automatically calculated: average peak velocity (APV) and diastolic-systolic velocity ratio (DSVR) for two cardiac cycles. CBF (ml/min) was calculated according to the following equation:
CBF = A x 0.5 x APV x 0.6
where A was the area of the vessel in the region of the Doppler measurements, APV — the average peak velocity, recorded by the system, 0.5 — the correction coefficient for parabolic flow, and 0.6 — the coefficient to convert from mm2cm/sec into ml/min.10,11 CFVR was calculated automatically using the following equation:
CFVR = APVh/APVr
where APVh was the average peak velocity after 18 µg of IC adenosine infusion (maximal hyperemia), and APVr — the average peak velocity before adenosine (rest).
The CFR was calculated from the CBF (ml/min) during adenosine-induced maximal hyperemia (CBFh) and CBF at rest (CBFr):
CFR = CBFh/ CBFr
The total coronary vessel resistance index (TCVRI) and the minimal coronary vessel resistance index (MCVRI) were calculated as a ratio between the MABP and the CBF before (CBFr) and after IC adenosine administration (CBFh), respectively:
TCVRI = MABP/CBFr
MCVRI = MABP/CBFh
Quantitative coronary angiography (QCA). Quantitative estimation of coronary artery dimensions was conducted by QCA using CMS®, version 0.3 (MEDIS, Medical Imaging Systems, BV, Leiden, The Netherlands).12,13 The following parameters were recorded: minimal lumen diameter (MLD) and minimal lumen area (MLA), reference segment diameter (RSD) and reference segment area (RSA), % diameter stenosis (DS) and % area stenosis (AS).
Coronary artery measurements were assessed in the basal condition and after achieving a stable blood pressure decrease with NTP and NTG infusions.
Statistical analysis. Data were processed with SPSS, version 13.0.1. The following statistical methods were applied: descriptive analysis for continuous variables; one-sample Kolmogorov-Smirnov test to check the type of distributions of continuous variables; ANOVA with post hoc test with coefficients of Bonferoni to compare variables in the tree conditions — baseline, NTP and NTG infusions and correlation analysis to evaluate the correlation between CFR and CFVR. A p-value < 0.05 was considered significant.
Results
Effect of NTP and NTG on blood pressure and the double product. A significant increase in heart rate following NTP infusion compared to baseline was observed (Table 1). The systolic blood pressure decreased significantly by 27.59 ± 1.99% during NTP infusion and by 26.65 ± 1.94% during NTG infusion (p = NS for NTP vs. NTG). The diastolic pressure decreased significantly by 20.52 ± 1.65% and by 17.97 ± 1.80% with NTP and NTG infusions, respectively (p < 0.05 for NTP vs. NTG infusions). However, the difference between NTP and NTG infusions was not statistically significant with respect to the MABP (the perfusion pressure of the organs; 23.14 ± 1.91% and 22.65 ± 1.90% decrease, respectively; p = NS), nor was the double product (systolic blood pressure x heart rate; 25.21 ± 8.26% vs. 27.14 ± 7.23%; p = NS).
Effect of NTP and NTG on the epicardial coronary arteries. Only during NTG infusion was there a statistically significant increase of 18.02 ± 4.26% in the MLD and 42.69 ± 10.18% in the MLA (p < 0.05 vs. baseline) (Table 2). The RSD also increased significantly only during NTG infusion (p < 0.05 vs. baseline). Because of the parallel increase in the MLD and reference RSD, there was no change in the %DS. In the region of the vessel, where the sample volume of the Doppler FloWire was positioned, both NTP and NTG produced a significant increase in the artery diameter and area.
Effect on coronary flow.
a. Coronary flow velocity and volume
NTP and NTG infusions created a decrease in rest APV, but it was statistically significant only for NTG (by 9.75 ± 7.84% compared to baseline; p < 0.05)(Table 3). During hyperemia, there was no decrease in APV compared to baseline for both infusions. The calculated CBF was similar for the three conditions before and during hyperemia. A trend toward a higher hyperemic blood flow volume was recorded for NTP and more prominently for NTG. There was no change in CFR for both medications. A statistically significant increase in CFVR for the NTG infusion was recorded (Table 4). The hyperemic DSVR was less than the rest DSVR in all three conditions (baseline, NTP and NTG) and was higher for NTG compared to baseline and NTP (Table 3).
b. Coronary vessel resistance indices.
There was a significant decrease in coronary resistance after IC adenosine administration, reflecting the flow reserve for every condition (Table 5). Compared to baseline, there was a 22.18 ± 7.77% and 19.43 ± 10.03% reduction in the TCVRI and 25.00 ± 6.30% and 25.00 ± 8.81% in the MCVRI for NTP and NTG, respectively (all p < 0.05 vs. baseline). There were no differences between NTP and NTG infusions (Table 5).
Discussion
This study found that even a substantial arterial pressure drop created by IV infusions of NTP and NTG have no significant effect on CBF and CFR in patients with severe LAD artery narrowing. Both medications dilate epicardial coronary vessels. NTG dilates normal and stenotic arterial segments, since NTP predominantly affects the more distal non-stenotic vessels.
In the literature, there is a paucity of data concerning the effect of the pressure decrease overall and, in particular, after IV infusion of nitrates and NTP, on CBF and CFR in stenotic arteries. Most of the studies testing those agents treat only the morphological changes of the stenotic segment14 or changes in vessel diameter, blood flow and flow reserve in normal arteries.9,15–17
Epicardial coronary artery change. Braun et al have shown that sublingual NTG increases the area of the normal segments of the coronary artery by 18%, the moderately diseased segments by 22% and the severely stenotic segments by 36%.14 Feldman et al reported a similar dilation in normal coronary arteries produced by sublingual NTG and IV NTP with doses adjusted to create an equivalent decrease in the aortic pressure.18 According to Parham et al, IC NTP does not dilate normal epicardial arteries as assessed by QCA.8 In a previous study, we have shown that in normal arteries in humans, NTP, NTG and clonidine in a dose sufficient to decrease the mean blood pressure by 20%, produce an increase in the diameter of epicardial arteries.9 The response was qualitatively similar but quantitatively different (strongest dilation with NTG) for normal epicardial vessels.9 Our results were concordant with those of others.19 In the present study, only NTG significantly increased the MLD, MLA and RSD of the artery to a very similar degree. In the segment of the vessel where the Doppler wire sample volume was presumably positioned (a peripheral segment free of disease), there was a significant increase in the diameter/area for both agents, but more pronounced with NTG.
Coronary hemodynamics. Kern et al tested the effect of 50, 200 and 300 µg of IC NTG on CBF. They found a 74% flow increase in normal arteries and a 54% increase in stenotic arteries with 200 µg, and no further increase with 300 µg NTG.20 Recently, Parham et al reported a hyperemic effect of IC NTP equivalent to IC adenosine. The correlation was excellent for CFR and fractional flow reserve (FFR) in normal and stenotic arteries, respectively. At the highest dose (0.9 µg/kg bolus), there was a 20% decrease in the SABP and a 16% decrease in the DABP.8 In our previous study, only NTP increased the resting coronary flow, presumably because of dilation of arterioles, resulting in a decrease in CFVR with NTP, but no change with NTG.9 Rossen et al reported that administration of a 125 or 250 µg/kg bolus of IV diltiazem followed by a 5 µg/kg per minute infusion reduces the heart rate (77 ± 18 to 72 ± 17 bpm; p < 0.005) and MABP (96 ± 11 to 86 ± 15 mmHg; p < 0.005), while decreasing CFR from 3.9 ± 1.2 to 3.6 ± 1.1 (p < 0.01).21 IV diltiazem (10 mg) failed to improve reduced CFR in patients with microvascular angina, but left CFR unaffected.22 The 25% decrease in MABP in the present study resulted only in a decrease in rest APV with the NTG infusion. However, the blood flow volume remained the same due to a significant vessel area increase. The hyperemic APV and blood volume did not change with any of the medications, which means that IV infusions of NTP and NTG do not produce a decrease in blood flow to the myocardium, even in a region with a severe coronary lesion, despite a substantial decrease in the perfusion pressure. For the three conditions, IC adenosine produced an equivalent hyperemic flow, demonstrating no reduction in CFR during NTP and NTG infusions. This is a very important difference between IV and IC administration: IC NTP and NTG boluses produce significant hyperemia, but IV infusions do not, even if the changes in systemic hemodynamics are similar. In our study, coronary autoregulation was preserved despite the arterial pressure drop. We speculate that the preservation of CBF and CFR may be a result of the dilatory effects of the medications (especially NTG) on the stenotic segment. At the same time, obviously there was a reduction in myocardial oxygen requirements because of the decreased preload, afterload and myocardial wall stress.
The decrease in DSVR during adenosine-induced hyperemia was a finding we did not see in the literature. The predominance of the diastolic component of coronary flow is believed to be a result of the compression of intramural arterioles and venules during ventricular systole.23,24 The transition to a predominantly systolic flow indicates a greater contribution of the epicardial vessels to coronary resistance and thus a hemodynamically significant lesion.25 We speculate that the decrease in diastolic filling during hyperemia represents a greater relative epicardial contribution to coronary resistance as a result of the dilation of small, resistant arteries. Only NTG favorably affects this ratio, which was significantly greater during hyperemia compared to baseline and NTP, a finding also reported by others.26
Coronary artery resistance changes represent a major part of coronary autoregulation.27 In the present study, we have shown a decrease in both the total and minimal coronary vessel resistance indices as a result of decreased mean coronary pressure and preserved blood flow. Total and minimal vessel resistance decreased as a result of dilation of both the epicardial and small vessels. According to the Hagenbach-Poiseuille equation, in severely stenotic lesions, even a small increase in MLD will cause a critical drop in coronary resistance.24,28 We have demonstrated such an increase in MLD with NTG and non-significant dilation with NTP. Because of the decrease in ventricular wall stress, a decrease in resistance in the segment capillaries-venules-veins is logical.29
Study limitations. There are some limitations in measuring CBF and CFR when using a Doppler wire. The position of the wire may change and the signal as well. The equation for blood flow calculation assumes a circular cross-section of the vessel, which in many cases may not be true. Despite our efforts to create the same hemodynamic conditions while comparing the net effect of NTP and NTG, some differences occurred in heart rate and diastolic blood pressure during the infusions. However, in our view, the most important parameters, MABP and double product, were equal. Our precaution to maintain an identical heart rate with right atrial pacing is methodologically correct, but does not necessarily apply to everyday clinical practice. The narrow inclusion/exclusion criteria and very high complexity of the study protocol led to the limited number of patients included. However, some obvious tendencies in the effects of NTP and NTG on coronary artery morphology and blood flow could be delineated.
Conclusion
Our results show that in patients with severe single-vessel coronary atherosclerotic lesions, IV infusion of NTP and NTG, in a dose adequate to produce a 25% drop in mean arterial pressure, does not lead to any appreciable decrease in the CBF or CFR. All of this was observed in situations of decreased myocardial stress, which in turn could result in a better balance between myocardial oxygen requirement and supply. Thus, no hesitation should be shown for the use of either drug in patients with obstructive coronary artery disease, even if they produce an appreciable drop in blood pressure.
