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(Circulation. 1995;92:2109-2112.)
© 1995 American Heart Association, Inc.

Articles

Limb Vasoconstriction After Successful Angioplasty of the Left Anterior Descending Coronary Artery

Ciro Indolfi, MD; Federico Piscione, MD; Roberto Ceravolo, MD; AntonGiulio Maione, MD; Amelia Focaccio, MD; Maria Assunta Rao, MD; Giovanni Esposito, MD; Mario Condorelli, MD; Massimo Chiariello, MD

From the Division of Cardiology, Department of Medicine, University Federico II, Napoli, Italy.

Correspondence to Ciro Indolfi, MD, Division of Cardiology, University Federico II, Via St Pansini 5, 80131 Napoli, Italy.

	Abstract

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Background Coronary vasoconstriction has been described after uncomplicated percutaneous transluminal coronary angioplasty (PTCA). However, it is still unknown whether this phenomenon is limited to coronary circulation. The present study was planned to assess the effects of a successful PTCA on forearm blood flow (FBF) and resistance. The role of -adrenoceptors and calcium antagonist agents on PTCA-induced limb blood flow changes was also investigated.

Methods and Results We prospectively studied 37 patients scheduled for elective single PTCA of the left anterior descending coronary artery. All patients had evidence of exercise-induced myocardial ischemia. All vasoactive drugs were withdrawn for at least 48 hours before the study. FBF was measured by calibrated venous occlusion plethysmography. A significant reduction of FBF was observed at 1, 5, and 15 minutes after PTCA (from 3.7±1.2 to 2.7±1.5, 3.0±1.6, and 2.9±1.9 mL/100 mL tissue per minute, respectively; all P<.05 versus baseline). Vascular forearm resistance also increased at 1, 5, and 15 minutes after PTCA (from 27±8 to 42±16, 37±10, and 43±19 U, respectively; all P<.05 versus baseline). Phentolamine (12 µg · kg^-1 · min^-1, n=7) or verapamil (3.5 µg · kg^-1 · min^-1, n=7) also was infused intra-arterially. PTCA-induced forearm vasoconstriction was completely abolished by pretreatment with regional infusion of phentolamine or verapamil.

Conclusions After an uncomplicated PTCA of the left anterior descending coronary artery, a reduction in FBF and an increase in forearm vascular resistance were observed. This peripheral vasoconstrictive response was probably due to -adrenergic stimulation and was abolished by intra-arterial infusion of calcium antagonist agents.

Key Words: angioplasty • blood flow • verapamil • receptors • adrenergic • alpha

	Introduction

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Spontaneous coronary artery vasoconstriction after percutaneous transluminal coronary angioplasty (PTCA) occurs routinely at and distal to the site of balloon dilation despite pretreatment with aspirin.^{1 2 3 4}

Previous studies suggested that the mechanism(s) responsible for this vasoconstriction might be related to the phenomenon of coronary autoregulation,¹ the release of vasoactive substances from aggregating platelets at the site of intimal injury,^{4 5} or sympathetic activation.^{2 6} However, it is still unknown whether this vasoconstriction is limited to the coronary circulation. Demonstration of the presence or absence of the vasoconstriction after PTCA in the forearm vasculature might be important to clarification of this phenomenon.

We recently reported a pronounced reduction in coronary and forearm blood flow (FBF) after regional ₁- or ₂-adrenoceptor stimulation.^{7 8} Activation of cardiac sympathetic afferents has also been described extensively during myocardial ischemia in different animal preparations^{9 10 11} and humans.¹² In a previous study, we demonstrated that after PTCA a significant vasoconstriction occurs in a vessel distal to a dilated stenosis and in the control coronary segment not manipulated by the guide wire or balloon catheter.² Because this vasoconstriction was abolished by pretreatment with intracoronary phentolamine, we hypothesized that significant -adrenoceptor–mediated coronary vasoconstriction occurs after balloon dilation.² Thus, neural and hormonal mechanisms may participate in the coronary constriction associated with an uncomplicated coronary angioplasty.

The aim of this study was to test this hypothesis by examining the effects of uncomplicated PTCA of the left anterior descending coronary artery (LAD) on FBF and vascular resistance.

	Methods

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Population
Thirty-seven patients (34 men and 3 women, 43 to 72 years of age [mean, 54.6±8.4 years]) scheduled for elective single lesion angioplasty of the LAD were prospectively included in the study. The study was approved by the Institutional Review Board of the University of Naples, and written informed consent was obtained from all patients before the study. No patients had unstable angina, angina at rest, previous or acute myocardial infarction, diabetes mellitus, hypertrophic cardiomyopathy, systemic hypertension, congestive heart failure, visible collateral circulation, or high plasma cholesterol levels. All patients had evidence of exercise-induced myocardial ischemia despite medical therapy. We included only patients from whom we could withdraw all vasoactive drugs for at least 48 hours before the study. No premedication was given before the procedure.

All patients underwent catheterization of the right and left sides of the heart in the morning, after an overnight fast. After a local anesthesia was administered, femoral arterial (8F) and femoral venous (7F) sheaths were placed, and 5000 U IV heparin was given. Diagnostic coronary angiograms were performed by a standard percutaneous femoral approach with the Judkins technique. After diagnostic coronary angiographies were obtained to select the best projection (in which the stenosis was dilated and the distal and control vessels were recorded), a second bolus of heparin (5000 U IV) was administered, followed by 500 mg IV acetylsalicylic acid and lysine salt. The angioplasties were performed by use of an over-the-wire balloon catheter system. Balloon size was chosen to match the diameter of the "normal" coronary segment adjacent to the stenosis to be dilated, which is common during routine angioplasty. The inflation time of the balloon was always 90 seconds.

Study Protocol
Baseline FBF was measured twice at 15 and 30 minutes after the end of the diagnostic angiography. FBF was measured 1, 5, and 15 minutes after balloon deflation (n=23). In 14 patients, the same protocol was performed during intra-arterial continuous infusion of phentolamine (n=7) or verapamil (n=7). In these groups of patients, the brachial artery was cannulated under local anesthesia with 2% (wt/vol) procaine with a 20-gauge polyethylene catheter (Vasculon 2), and phentolamine (12 µg · kg^-1 · min^-1) or verapamil (3.5 µg · kg^-1 · min^-1) was infused by a Harvard pump to keep the flow rate <0.8 mL/min.

Aortic pressure and heart rate were measured in the control state and 5 and 15 minutes after PTCA and recorded by a computer-aided system for cardiac catheterization (Siecor, Siemens). Pressure waveform analysis was performed within a user-definable analysis window over eight consecutive beats.¹³

FBF Measurement
The studies were conducted at a constant temperature of 20°C to 24°C. Forearm volume was determined by water displacement before the study. FBF was measured with a mercury-in-Silastic-rubber strain gauge applied around to the left forearm supported above heart level.^{7 8 9 10 11 12 13 14} The gauge was connected to a calibrated plethysmograph (Vasculab, model SPC 16, Meda Sonics), which was connected to a strip-chart recorder to record flow measurements in the forearm. A venous occlusion pressure of 40 mm Hg was used in the upper arm cuff, and FBF was measured as the slope of the change in forearm volume.⁷ The mean of at least three measurements was obtained at each time point. Forearm vascular resistance was calculated by dividing the mean blood pressure (in millimeters of mercury) by FBF and was expressed in units. Mean blood pressure was calculated by adding one third of the difference between systolic and diastolic pressures to the diastolic pressure.

Statistical Analysis
Results are expressed as mean±SD. Statistical analysis was performed by ANOVA for repeated measures by use of a SYSTAT program.¹⁵ When a significant overall effect was detected, Tukey's test was applied to compare single mean values.¹⁶ Comparisons of FBF data between the two groups were done by two-way ANOVA. Significant differences were assumed to be present when P<.05.

	Results

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Twenty-nine patients experienced angina pectoris, and 30 patients showed ST-segment changes during balloon inflation. The systolic aortic pressure did not change significantly 1, 5, and 15 minutes after PTCA (from 135±18 to 138±19, 136±19, and 134±17 mm Hg, respectively); neither did the diastolic and mean aortic pressures. Heart rate was also unchanged 1, 5, and 15 minutes after PTCA (from 70±6 to 71±7, 69±8, and 69±8 beats per minute, respectively).

Effects of PTCA on FBF and Resistance
No significant variations in FBF or resistance were detected in the 15-minute period immediately preceding balloon inflation. Fig 1 (top) shows the FBF changes after PTCA. At 1, 5, and 15 minutes after PTCA, FBF was reduced from 3.7±1.2 to 2.7±1.5, 3.0±1.6, and 2.9±1.9 mL/100 mL tissue per minute (-27%, -19%, and -22% versus baseline, respectively; all P<.05). Calculated forearm vascular resistance increased in response to PTCA from 27±7 to 42±16, 37±10, and 43±19 U at 1, 5, and 15 minutes after PTCA, respectively (all P<.05 versus baseline; Fig 1, bottom).

View larger version (15K): [in this window] [in a new window]   Figure 1. Graphs showing the effect of percutaneous transluminal coronary angioplasty (PTCA) on forearm blood flow (FBF; top) and vascular resistance (bottom). No variations in FBF or resistance were observed in the 15-minute period immediately preceding the balloon inflation (B1 indicates baseline 1; B2, baseline 2). A significant peripheral vasoconstriction was observed after PTCA. *P<.05 vs baseline.

In contrast, in patients treated with intra-arterial infusion of phentolamine, an increase in FBF was observed: from 4.1±1.0 to 6.7±10 mL/100 mL tissue per minute before PTCA (P=NS) and to 8.8±2.6, 8.0±2.1, and 8.7±1.3 mL/100 mL tissue per minute at 1, 5, and 15 minutes after PTCA, respectively (P<.05; Fig 2, top), whereas forearm resistance decreased from 22.9±2.7 to 14.4±3.0 U before PTCA (P=NS) and to 12.0±3.7, 13.1±5.6, and 11.3±3.6 U at 1, 5, and 15 minutes after PTCA, respectively (P<.05; Fig 2, bottom).

View larger version (15K): [in this window] [in a new window]   Figure 2. Graphs showing the effect of pretreatment with phentolamine (P) on percutaneous transluminal coronary angioplasty (PTCA)–induced changes in forearm blood flow (FBF; top) and vascular resistance (bottom). In patients pretreated with intra-arterial phentolamine, an increase in FBF was observed after PTCA. B1 indicates baseline 1; B2, baseline 2. *P<.05 vs baseline.

Intra-arterial infusion of verapamil also completely abolished PTCA-induced limb vasoconstriction. The FBF increased after verapamil infusion from 3.9±1.5 to 16.0±2.6 mL/100 mg tissue per minute before PTCA (P<.05) and to 19.0±6.0, 19.0±5.3, and 20.0±5.0 mL/100 mg tissue per minute at 1, 5, and 15 minutes after PTCA, respectively (P<.05; Fig 3, top). After PTCA, the FBF and vascular resistance were not significantly changed compared with the values after verapamil infusion (Fig 3).

View larger version (16K): [in this window] [in a new window]   Figure 3. Graphs showing the effect of the calcium antagonist agent verapamil (V) on forearm blood flow (top) and vascular resistance (bottom) after percutaneous transluminal coronary angioplasty. B1 indicates baseline 1; B2, baseline 2. *P<.05 vs baseline.

	Discussion

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The primary finding of the present study is that an uncomplicated PTCA of the LAD induced a reduction in FBF.

Several studies described distal coronary vasoconstriction after coronary angioplasty.^{1 2 3 4 6 17} However, it is unknown whether this phenomenon is limited to coronary circulation.

Our study, performed in patients with a single LAD stenosis during pharmacological washout, demonstrates for the first time that significant vasoconstriction also occurs in the forearm vessels. We previously showed that after successful PTCA a coronary constriction occurs not only in the segment distal to the dilated stenosis but also in the control coronary segment not manipulated by the catheter or guide wire.² This finding was also confirmed by other investigators.⁶ The present study definitely demonstrates that a systemic vasoconstriction occurs after PTCA.

Mechanisms of Coronary and Forearm Vasoconstriction After PTCA
The first and probably the most important mechanism of generalized vasoconstriction after PTCA is related to the sympathetic stimulation induced by PTCA. The temporary coronary occlusion during coronary angioplasty may be associated with anginal pain, ischemic ST changes, regional wall motion abnormalities, and elevation of norepinephrine levels. An increase in plasma norepinephrine levels after PTCA was found in a previous study.¹⁸ The cardiac spillover of noradrenaline did not change during balloon occlusion but increased almost threefold during early reperfusion.¹⁸ Activation of arterial wall stretch receptor is another potential source of cardiac afferent neural activity.¹⁹

Several studies have demonstrated that both ₁- and ₂-adrenoceptors mediate constriction of epicardial coronary arteries.^{8 20 21 22 23 24} The presence of ₁- and ₂-adrenoceptor–mediated vasoconstriction was also documented in peripheral human vessels.^{7 25 26} Therefore, the increase in circulating catecholamine- and neuronal-mediated sympathetic tone may induce coronary and peripheral vasoconstriction after PTCA through –adrenoceptor stimulation. On the other hand, the increased concentration of vasoactive substances released from platelets has been indicated as another explanation for PTCA-induced coronary vasoconstriction.^{5 17}

It is unlikely, however, that this is the primary mechanism responsible for PTCA-induced limb vasoconstriction. In fact, although serotonin is released during coronary angioplasty and may cause coronary vasoconstriction,¹⁷ it is rapidly inactivated by the lungs.²⁷ Therefore, it is unlikely that serotonin produces vasoconstriction in the forearm circulation. Finally, thromboxane concentration does not increase in the coronary sinus after PTCA.²⁸ On the other hand, after –adrenoceptor blockade, a forearm vasodilation was observed after PTCA, suggesting activation of unblocked ß-adrenoceptors.²⁹

Study Limitations and Advantages
We studied our patients in the morning (between 8 AM and 1 PM). A circadian rhythm in basal vascular tone, caused either partly or entirely by -adrenoceptor sympathetic vasoconstrictor activity during the morning, has been described.¹⁴ Therefore, a more pronounced vasoconstriction might be present in the afternoon.

In the present study, we used venous occlusion plethysmography, which is an accurate and reliable method to quantify the actual FBF changes in humans.^{7 14}

Conclusions
The present study demonstrated that forearm vasoconstriction occurs after balloon occlusion that is completely abolished by calcium-antagonist or -adrenergic blockade agents. This -adrenergic vasoconstriction after PTCA could result from both direct sympathetic nerve outflow and circulating catecholamines. Although the significance of this peripheral vascular response after PTCA is still unclear, this vasoconstrictive adaptation may represent an important component of the increased sympathetic discharge associated with coronary occlusion and may play a role in the maintenance of systemic blood pressure during and after coronary occlusion.

	Acknowledgments

 
We thank Salvatore Buonerba, Giuseppe D'Alise, and Arturo Bruno for excellent technical assistance.

Received December 12, 1994; revision received April 19, 1995; accepted May 13, 1995.

	References

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