Intracoronary Isosorbide Dinitrate Research Articles

Thrombolysis in Myocardial Infarction Frame Count for Coronary Blood Flow Evaluation during Interventional Diagnostic Procedures.

Background and Objectives: An interventional diagnostic procedure (IDP), including intracoronary acetylcholine (ACh) provocation and coronary physiological testing, is recommended as an invasive diagnostic standard for patients suspected of ischemia with no obstructive coronary arteries (INOCA). Recent guidelines suggest Thrombolysis In Myocardial Infarction frame count (TFC) as an alternative to wire-based coronary physiological indices for diagnosing coronary microvascular dysfunction. We evaluated trajectories of TFC during IDP and the impact of ACh provocation on TFC. Materials and Methods: This was a single-center, retrospective study. Patients who underwent IDP to diagnose INOCA were included and divided into two groups according to the positive or negative ACh provocation test. Wire-based invasive physiological assessment was preceded by ACh provocation tests and intracoronary isosorbide dinitrate (ISDN). We evaluated TFC at three different time points during IDP; pre-ACh, post-ISDN, and post-hyperemia. Results: Of 104 patients, 58 (55.8%) had positive ACh provocation test. In the positive ACh group, resting mean transit time (Tmn) and baseline resistance index were significantly higher than in the negative ACh group. Post-ISDN TFC was significantly correlated with resting Tmn (r = 0.31, p = 0.002). Absolute TFC values were highest at pre-ACh, followed by post-ISDN and post-hyperemia in both groups. All between-time point differences in TFC were statistically significant in both groups, except for the change from pre-ACh to post-ISDN in the positive ACh group. Conclusions: In patients suspected of INOCA, TFC was modestly correlated with Tmn, a surrogate of coronary blood flow. The positive ACh provocation test influenced coronary blood flow assessment during IDP.

A Pilot Evaluation Study of Diffuse Coronary Arterial Contraction Causing Ischemia by Double Measurement of Left Ventriculography Before and After Intracoronary Administration of Nitrates.

Background: Abnormal diffuse coronary artery contraction is not easily diagnosed. In order to evaluate its true risk, we performed double left ventriculography (LVG) before and after intracoronary administration of isosorbide dinitrate (ISDN). We also investigated the relationship between changes in coronary lumen area and changes in left ventricular ejection fraction (LVEF) after ISDN.Methods and Results: The study included 53 patients who underwent an acetylcholine (ACh) provocation test after coronary angiogram and LVG. The second LVG was performed after intracoronary ISDN administration. Coronary lumen area was measured by quantitative coronary arteriography (QCA). Simple and multiple regression analyses showed a significant correlation between changes in total QCA area before and after ISDN administration (pre-and post-total QCA area, respectively) and changes in LVEF. Using structural equation modeling, we observed a negative effect of pre-total QCA area and a positive effect of post-total QCA area on LVEF improvement. Importantly, LVEF improvement was similar between the ACh-positive and -negative groups on the coronary artery spasm test. Receiver operating characteristic curves indicated that the cut-off value at which changes in total QCA area affected changes in LVEF was 5%.Conclusions: Performing double LVG tests before and after ISDN administration may detect myocardial ischemia caused by diffuse coronary artery contraction. The addition of this method to the conventional ACh provocation test may detect the presence of local and/or global myocardial ischemia.

A case of vasospastic angina in which the ergonovine provocation test with intracoronary isosorbide dinitrate and nicorandil was effective in the diagnosis of microvascular spasm

A 60-year-old man was admitted with early morning angina while at rest. Coronary angiogram revealed no organic lesions; therefore, a spasm provocation test with ergonovine was performed. Administration of intracoronary ergonovine induced total occlusion of the right coronary artery. The induced total occlusion improved but coronary flow velocity remained severely reduced and chest discomfort with ST-T changes in ECG remained in spite of repeated administration of isosorbide dinitrate (ISDN). Intracoronary administration of nicorandil following ISDN alleviated the chest discomfort, normalized the ST-T change in ECG, and improved the coronary flow. This suggested that microvascular spasm and the epicardial spasm were not relieved by ISDN but by nicorandil. Intracoronary nicorandil injection following ISDN administration may be useful for the diagnosis of microvascular spasm in the ergonovine provocation test.

Unusual Vasospastic Angina: A Documented Asymptomatic Spasm with Normal ECG-A Case Report and a Review of the Literature.

We report the case of a 53-years-old patient, known to have coronary artery disease, presenting with typical angina at rest with normal ECG and laboratory findings. His angina is relieved by sublingual nitroglycerin. He had undergone a cardiac catheterisation two weeks prior to his presentation for the same complaints. It showed nonsignificant coronary lesions. Another catheterisation was performed during his current admission. He developed coronary spasm during the procedure, still with no ECG changes. The spasm was reversed by administration of 2 mg of intracoronary isosorbide dinitrate. Variant (Prinzmetal's) angina was diagnosed in the absence of electrical ECG changes during pain episodes.

Isolated Cardiac Involvement of B-Cell Acute Lymphoblastic Leukemia Mimicking Acute Myocardial Infarction With Persistent Broad ST-Segment Elevation

A 61-year-old Japanese woman with a previous history of complete remission of precursor B-cell acute lymphoblastic leukemia for 3 years presented to our hospital with severe chest pain. Persistent broad anterior ST-segment elevation was noted on the 12-lead ECG (Figure 1A). Troponin T level was slightly elevated to 1.190 ng/mL (normal, <0.1 ng/mL). She was referred for urgent coronary angiography, which revealed no significant stenosis (Figure 2). Despite intracoronary isosorbide dinitrate administration, the ST-segment elevation did not normalize to the baseline (Figure 1B). Circulatory assistance with intra-aortic balloon pumping was required to maintain her circulation. An echocardiogram revealed a dense thick mass in the right atrioventricular groove extending into the right ventricular free wall, left ventricular wall, and pericardium (Figure 3A and online-only Data Supplement Movies IA and IB). Enhanced computed tomography imaging showed direct infiltration of an abnormal mass occupying the myocardium and pericardium, which filled the area around the root of …

Abstract 8768: Involvement of Rho-Kinase Activation in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stents in Patients with Coronary Artery Disease

Background: We have previously demonstrated that activation of Rho-kinase, the effector of the small GTP-binding protein Rho, plays a central role in the pathogenesis of coronary vasospasm in pigs and humans and coronary hyperconstricting responses following drug-eluting stent (DES) implantation in pigs. In this study, we further examined whether Rho-kinase activation is also involved in the DES-induced coronary hyperconstricting responses in humans. Methods: We examined 25 patients with coronary artery disease who underwent coronary intervention with either DES (n=16, sirolimus/paclitaxel 15/1, M/F 10/6, 69 ± 11[SD] years) or bare-metal stents (BMS, n=9, M/F 7/2, 70 ± 8 years). We examined coronary vasoconstricting responses to intracoronary (IC) acetylcholoine (ACh) before and after the intracoronary treatment with a Rho-kinase inhibitor, fasudil (300 μ g/min for 15 min). We evaluated coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT). Results: QCA showed that the coronary vasoconstricing responses to ACh were significantly enhanced in the DES group compared with the BMS group at both the proximal (BMS -13.0 ± 10.7% vs. DES -24.7 ± 14.2[SD] %, P&lt;0.05) and the distal segments (BMS -24.4 ± 12.2%, DES -42.8 ± 14.8%, P&lt;0.01). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal -10.2 ± 11.3%, distal -14.2 ± 10.2% vs. before fasudil, both P&lt;0.01). In contrast, coronary vasodilator responses to intracoronary isosorbide dinitrate were comparable between the 2 groups. Although OCT showed a variable degree of intimal thickening at the segments adjacent to DES, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. Conclusion: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD as well, suggesting the therapeutic importance of Rho-kinase pathway.

Rapid Progression of Coronary Atherosclerosis by Coronary Artery Spasm Leading to Acute Coronary Syndrome

HomeCirculationVol. 119, No. 16Rapid Progression of Coronary Atherosclerosis by Coronary Artery Spasm Leading to Acute Coronary Syndrome Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBRapid Progression of Coronary Atherosclerosis by Coronary Artery Spasm Leading to Acute Coronary Syndrome Ichiro Sakamoto, Masahiro Mohri and Hideo Yamamoto Ichiro SakamotoIchiro Sakamoto From the Department of Cardiology, Kyushu Kosei-Nenkin Hospital, Kitakyushu, Japan. Search for more papers by this author , Masahiro MohriMasahiro Mohri From the Department of Cardiology, Kyushu Kosei-Nenkin Hospital, Kitakyushu, Japan. Search for more papers by this author and Hideo YamamotoHideo Yamamoto From the Department of Cardiology, Kyushu Kosei-Nenkin Hospital, Kitakyushu, Japan. Search for more papers by this author Originally published28 Apr 2009https://doi.org/10.1161/CIRCULATIONAHA.108.839522Circulation. 2009;119:2233–2234A 67-year-old normotensive, normolipidemic man presented with short-lasting chest pain followed by syncope. Intracoronary ergonovine maleate (40 μg) provoked a severe spasm in the middle portion of right coronary artery (Figure 1A and 1B, arrow), but there was no significant (>50%) right or left coronary artery disease after intracoronary nitrates (Figure 1C). The patient was diagnosed as having vasospastic angina. Download figureDownload PowerPointFigure 1. Right coronary arteriograms before (A) and after intracoronary ergonovine (B) and isosorbide dinitrate (ISDN; C).Three years later, he presented with sustained, nitroglycerin-resistant chest pain at our emergency room. Emergent coronary arteriography revealed a high-grade stenosis where coronary spasm had been documented earlier (Figure 2A, arrow). Intracoronary administration of isosorbide dinitrate improved distal filling but failed to dilate the stenosed segment (Figure 2B). Intravascular ultrasound confirmed coronary plaque at that segment (Figure 2B, inset), and a bare metal stent was successfully implanted (Figure 2C). Serial changes in serum enzymes confirmed the diagnosis of acute non–ST-elevation myocardial infarction. Download figureDownload PowerPointFigure 2. Right coronary arteriograms before (A) and after intracoronary isosorbide dinitrate (ISDN; B) and percutaneous coronary intervention (PCI; C).Although coronary spasm has been implicated to cause atherosclerosis progression over years,1 there are few reports demonstrating a critical role of coronary artery spasm in rapid plaque progression and the development of acute coronary syndrome. Because there was no disease progression in left coronary artery segments, it was assumed that focal spasm might have contributed to a ruptured atheromatous plaque in our patient, leading eventually to myocardial infarction. Previous experimental studies have shown that coronary artery spasm could cause intraplaque hemorrhage and acute myocardial infarction in the swine model.2 Thus, coronary vasospasm may play an important role in the pathogenesis of not only variant angina but also acute coronary syndrome, as seen in this patient.DisclosuresNone.FootnotesCorrespondence to Masahiro Mohri, MD, PhD, Department of Cardiology, Kyushu Kosei-Nenkin Hospital, 1-8-1 Kishinoura, Kitakyushu 806-8501, Japan. E-mail [email protected]References1 Nobuyoshi M, Tanaka M, Nosaka H, Kimura T, Yokoi H, Hamasaki N, Kim K, Shindo T, Kimura K. Progression of coronary atherosclerosis: is coronary spasm related to progression? J Am Coll Cardiol. 1991; 18: 904–910.CrossrefMedlineGoogle Scholar2 Kuga T, Tagawa H, Tomoike H, Mitsuoka W, Egashira S, Ohara Y, Takeshita A, Nakamura M. Role of coronary artery spasm in progression of organic coronary stenosis and acute myocardial infarction in a swine model: importance of mode of onset and duration of coronary artery spasm. Circulation. 1993; 87: 573–582.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kim J, Park J, Yang Y, Lee S, Kim D, Song J, Kang D, Park S, Park S and Song J (2022) Percutaneous coronary intervention in patients with documented coronary vasospasm during long-term follow-up, Heart, 10.1136/heartjnl-2021-320645, 108:16, (1303-1309), Online publication date: 1-Aug-2022. Mori H, Takahashi J, Sato K, Miyata S, Takagi Y, Tsunoda R, Sumiyoshi T, Matsui M, Tanabe Y, Sueda S, Momomura S, Kaikita K, Yasuda S, Ogawa H, Shimokawa H and Suzuki H (2020) The impact of antiplatelet therapy on patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association, IJC Heart & Vasculature, 10.1016/j.ijcha.2020.100561, 29, (100561), Online publication date: 1-Aug-2020. Montenegro Sá F, Ruivo C, Graça Santos L, Antunes A, Soares F, Baptista J and Morais J (2018) Ultra-rapid progression of coronary artery disease or undiagnosed unstable plaque? A brief review from a case report, Revista Portuguesa de Cardiologia (English Edition), 10.1016/j.repce.2018.02.016, 37:3, (259-264), Online publication date: 1-Mar-2018. Montenegro Sá F, Ruivo C, Graça Santos L, Antunes A, Campos Soares F, Baptista J and Morais J (2018) Progressão ultrarrápida de doença coronária ou placa instável não detetada?, Revista Portuguesa de Cardiologia, 10.1016/j.repc.2017.04.005, 37:3, (259-264), Online publication date: 1-Mar-2018. Shah P, Bajaj S, Virk H, Bikkina M and Shamoon F (2015) Rapid Progression of Coronary Atherosclerosis: A Review, Thrombosis, 10.1155/2015/634983, 2015, (1-6), Online publication date: 28-Dec-2016. April 28, 2009Vol 119, Issue 16 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.108.839522PMID: 19398679 Originally publishedApril 28, 2009 PDF download Advertisement SubjectsAcute Coronary Syndromes

Comparison of intracoronary adenosine and isosorbide dinitrate on no-reflow/slow flow during rotational atherectomy

Objective — To compare the effect of intracoronary adenosine and isosorbide dinitrate (ISDN) on no-reflow/slow flow during high-speed rotational atherectomy (HSRA) in patients with complex coronary artery disease (CAD).Methods and results — Medical records from consecutive patients diagnosed with complex CAD between November 2002 and March 2006 who underwent HSRA at the Tri-Service General Hospital, National Defence Medical Centre in Taipei, Taiwan, were included in this study. Patients in the adenosine group (n = 32) received a 50 mg intracoronary adenosine bolus prior to the initiation of burr rotation and during each ablation. Patients in the ISDN group (n = 58) received a 0.5 mg intracoronary ISDN bolus at comparable time points. Angiographic success was achieved in 100% of patients in the adenosine group and 98.3% (57/58) in the ISDN group.The procedural success rates were 96.9% (31/32) in the adenosine group and 89.7% (52/58) in the ISDN group. One patient (3.1%) from the adenosine group and six patients (10.3%) from the ISDN group experienced no-reflow/slow flow (P = 0.414). No in-hospital mortality occurred and target vessel revascularization was unnecessary.Conclusions — Intracoronary administration of either adenosine or ISDN during HSRA appears safe and administration of either agent may be effective in decreasing the incidence of no-reflow/slow flow during HSRA. Further large, prospective, randomized, placebo-controlled trials are required.

Initial evidence for the return of coronary vasoreactivity following the absorption of bioabsorbable magnesium alloy coronary stents

To investigate the endothelium independent coronary smooth muscle vasomotor function four months after implantation of magnesium alloy absorbable metal stents (AMS) as part of the Progress-AMS clinical trial (n = 5), compared with a control group of patients implanted with permanent metal stents (PMS) (n = 10) undergoing follow-up angiography, but who were free from angiographic restenosis. Quantitative coronary angiogram (QCA) using an automated edge detection system was performed before and after the administration of 2 mg intracoronary isosorbide dinitrate (ISDN). The vessel diameter was measured at 0.2 mm intervals throughout the stented segments and a 1 cm proximal reference segment. The cross sectional area (CSA) was calculated before and after the ISDN, averaged and the percentage change measured. Reference segments demonstrated preserved vasomotor function in all cases: +13.28% (AMS) versus +17.15% (PMS), p = 0.39. The mean percentage increase in CSA for the stented segment was +6.78% for the AMS versus -1.30% for PMS, p = 0.003. These data demonstrate that four months after AMS implantation vasomotor function in reference segments is no different to that observed with PMS. However in contrast to PMS, within the AMS-stented segments there is demonstrable vasodilatation. These observations may have important implications for future stent design.

Shortening of the ventricular fibrillatory intervals after administration of verapamil in a patient with Brugada syndrome and vasospastic angina

A 43-year-old man presented with electrocardiographic findings consistent with Brugada syndrome. Though the baseline coronary angiogram was normal, intracoronary infusion of ergonovine maleate caused complete occlusion of the left anterior descending and a 99% occlusion of the proximal right coronary artery, each relieved by intracoronary isosorbide dinitrate. Double extrastimuli delivered at the right ventricular outflow tract induced ventricular fibrillation terminated by a 200-J shock. Verapamil, 10 mg IV, increased ST-segment elevation and programmed stimulation repeated after the drug induced ventricular fibrillation with shorter F-F intervals and lower amplitude signals, which was not terminated by 200 J and required an additional 360-J shock. Ca 2+ antagonism may have been adverse in this patient with Brugada syndrome because the drug has the potential to increase the voltage gradient through the right ventricle and to slow intraventricular conduction at very fast heart rates.

Coronary Microvascular Dysfunction in Patients With Microvascular Angina

We have previously reported that angina pectoris persists in patients with coronary microvascular spasm (MVS) even on calcium channel blockers. Because measurement of myocardial lactate production in the coronary sinus is necessary to diagnose MVS, a more feasible diagnostic method needs to be developed. In this study, we examined the diagnostic significance of Thrombolysis in Myocardial Infarction (TIMI) frame count, a marker of coronary blood flow, in 131 consecutive patients who underwent provocation test for coronary spasm with acetylcholine (ACh). Epicardial coronary spasm (ES) was diagnosed as more than 75% of ACh-induced vasoconstriction noted by coronary angiography. MVS was diagnosed as ACh-induced myocardial ischemia (chest pain, ischemic ECG changes, and myocardial lactate production) without ES. TIMI frame count was significantly increased in patients with MVS alone (n = 35) and those with ES + MVS (n = 16) compared with those with ES alone (n = 53) or those with no myocardial ischemia (Normal, n = 27) either before and after intracoronary ACh and even after intracoronary isosorbide dinitrate (ISDN) in both the left anterior descending (LAD) and the left circumflex coronary artery (LCX). TIMI frame count in LAD correlated well to that in LCX in patients with MVS, suggesting diffuse impaired coronary microcirculation in the myocardium. These results suggest that increased TIMI frame count in response to ACh reflects microvascular dysfunction in MVS and that ISDN may not be enough to relieve MVS. Thus, TIMI frame count may be useful to diagnose MVS without requiring coronary sinus catheterization or myocardial lactate production measurement.

Use of simultaneous pressure and velocity measurements to estimate arterial wave speed at a single site in humans

It has not been possible to measure wave speed in the human coronary artery, because the vessel is too short for the conventional two-point measurement technique used in the aorta. We present a new method derived from wave intensity analysis, which allows derivation of wave speed at a single point. We apply this method in the aorta and then use it to derive wave speed in the human coronary artery for the first time. We measured simultaneous pressure and Doppler velocity with intracoronary wires at the left main stem, left anterior descending and circumflex arteries, and aorta in 14 subjects after a normal coronary arteriogram. Then, in 10 subjects, serial measurements were made along the aorta before and after intracoronary isosorbide dinitrate. Wave speed was derived by two methods in the aorta: 1) the two-site distance/time method (foot-to-foot delay of pressure waveforms) and 2) a new single-point method using simultaneous pressure and velocity measurements. Coronary wave speed was derived by the single-point method. Wave speed derived by the two methods correlated well (r = 0.72, P < 0.05). Coronary wave speed correlated with aortic wave speed (r = 0.72, P = 0.002). After nitrate administration, coronary wave speed fell by 43%: from 16.4 m/s (95% confidence interval 12.6-20.1) to 9.3 m/s (95% confidence interval 6.5-12.0, P < 0.001). This single-point method allows determination of wave speed in the human coronary artery. Aortic wave speed is correlated to coronary wave speed. Finally, this technique detects the prompt fall in coronary artery wave speed with isosorbide dinitrate.

Relationship between plasma oxidized low-density lipoprotein and the coronary vasomotor response to acetylcholine in patients with coronary artery disease.

The present study examined the relation of plasma oxidized low-density lipoprotein (LDL) levels to plasma LDL cholesterol levels and the impairment of endothelium-dependent coronary vasorelaxation in patients with coronary artery disease (CAD). In the first study, the relationship between plasma levels of oxidized LDL and LDL cholesterol were investigated in 88 patients with CAD. In the second study, the changes in the diameter of the left anterior descending (LAD) and the left circumflex (LCX) coronary arteries were measured after intracoronary administration of acetylcholine (15 microg) and isosorbide dinitrate (2.5 mg) in 15 patients with CAD. Plasma oxidized LDL levels were determined with a sandwich enzyme-linked immunosorbent assay. Plasma oxidized LDL levels did not correlate with plasma LDL cholesterol levels (r=-0.03, p=NS). The % diameter changes (mean+/-SEM) in the LAD and LCX after intracoronary acetylcholine were -8.3+/-3.5% and -10+/-4.2%, respectively. The % diameter changes in the LAD and LCX after intracoronary isosorbide dinitrate were 23+/-4.8% and 23+/-5.1%, respectively. The % diameter changes in the LAD and LCX inversely correlated with plasma oxidized LDL levels after intracoronary acetylcholine (LAD: r=-0.55, p=0.03; LCX: r=-0.59, p=0.02), but were not after intracoronary isosorbide dinitrate. Plasma LDL cholesterol, triglyceride, and high-density lipoprotein cholesterol levels did not correlate with the coronary vasoreaction to acetylcholine. In conclusion, plasma oxidized LDL levels do not correlate with plasma LDL-cholesterol levels and are related to impairment of endothelium-dependent coronary vasodilation in patients with CAD.

Morphological and functional changes in coronary vessel evoked by repeated endothelial injury in pigs.

We examined the morphological changes induced by repeated endothelial denudation in coronary artery (CA), as well as functional changes in the endothelium-dependent and smooth muscle responses to various vasoactive agents during the process of intimal thickening. We observed vascular responses in denuded and non-denuded portions of pig CA while being fed a normal diet (n = 11, N group) or 2% cholesterol diet (n = 25, C group) to intracoronary acetylcholine (ACh), 5-hydroxytryptamine (5-HT), substance P (SP), and isosorbide dinitrate (ISDN) with and without the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg i.v.) over a period of 8 weeks. Balloon endothelial denudation of the left anterior descending CA was carried out every 2 weeks. In N group, maximum vasoconstriction was obtained with ACh 2 weeks after the first denudation [26 +/- 5% vs. 1 +/- 1% pre-denudation, p < 0.05]. L-NAME did not affect ACh-induced CA diameter changes. Thereafter, the response to ACh was attenuated by repeated denudation in N groups. However, the degree of 5-HT-induced CA narrowing at the denuded portion increased from 7 +/- 4% (0 week) to 88 +/- 8% (8 weeks) (p < 0.05). The changes resulted in severe myocardial ischaemia, and suggested that endothelium-dependent vasodilation was progressively attenuated while hyperreactivity of vascular smooth muscle simultaneously increased. Vasodilation induced by SP was attenuated somewhat, but ISDN-induced vasodilation was preserved. Although mild hypercholesterolaemia was induced in C group, the vascular responses to these vasoactive agents did not differ from those of N group. Repeated CA endothelial injury and regeneration induce the change of morphology and vascular reactivity in the denuded portion regardless of atherogenic diet. This study strongly suggests that intimal thickening caused by repeated endothelial injury and regeneration induces specific vascular responses to vasoactive agents. Moreover, it is also suggested that during the progression of intimal thickening, increased vascular smooth muscle contraction and decreased endothelium-dependent dilation appear in a stimulus-dependent manner, often leading to severe coronary vasoconstriction accompanied with definitive ECG ST change.

How to standardize vasomotor tone in serial studies based on quantitation of coronary dimensions?

In patients with coronary artery disease including those after coronary bypass graft operation and heart transplantation intervention studies based on serial quantitative coronary angiography, in part combined with intravascular ultrasound, are of increasing relevance. Since vasomotor tone of epicardial coronary arteries is influenced by a variety of factors, angiographic follow-up studies require standardization of coronary tone by induction of maximal dilation. We reviewed the effects of the most potent coronary vasodilatory drug groups, calcium antagonists and nitrocompounds, on coronary diameters. Intravenous or intracoronary injections of verapamil, diltiazem, nifedipine, nicardipine, and nisoldipine can cause profound coronary dilation which has been shown to be maximal with verapamil and nisoldipine. Shortcomings of calcium antagonists include short or unknown duration of action after bolus administration, severe drop in blood pressure, and lack of commercial availability of solutions for injection of many substances. Isosorbide dinitrate induces profound coronary dilation; however, after sublingual administration marked blood pressure decrease can occur, and the duration of action and ideal dose of intracoronary isosorbide dinitrate has not been investigated yet. Injections of molsidomine and its active metabolite, SIN-1, cause longlasting, reproducible, maximal coronary dilation, although only after a waiting period of at least 10 minutes; unfortunately, SIN-1 is only commercially available in France. Nitroglycerin induces reproducible maximal coronary dilation and is easy to administer sublingually or as intracoronary bolus injection with rapid onset of action and no major side effects. The short duration of action may require repeated administrations. To date, repeated intracoronary bolus injections of 0.1 mg nitroglycerin every 10 minutes seem to be the optimal known regimen for standardization of coronary vasomotor tone in serial angiographic studies. Further investigations in this field with old and new vasodilatory drugs are recommendable.

Variable coronary vasomotor responses to acetylcholine in patients with normal coronary arteriograms: evidence for localised endothelial dysfunction.

The vasomotor responses of the epicardial coronary arteries to acetylcholine were examined in patients with normal coronary arteries and chest pain. Quantitative angiography was used to measure minimum lumen diameter of proximal and distal coronary artery segments at baseline, during intracoronary infusion of acetylcholine (10(-7) - 10(-3) mol/l), and following an intracoronary bolus (2 mg) of isosorbide dinitrate. Coronary arteriograms were obtained in 15 patients (mean (SEM) age 48 (10) years) with normal coronary arteries and chest pain. In response to the low concentrations of acetylcholine (10(-7) - 10(-6) mol/1) 20 (61%) distal and 11 (41%) proximal segments showed dilatation (group 1), whereas 13 (39%) distal segments and 14 (52%) proximal segments showed constriction (group 2) (P < 0.05 v group 1). In group 1, the maximum dilatation induced by acetylcholine in the proximal and distal segments was 7.83 (1.19)% and 11.6 (2.2)% respectively. In group 2, the maximum constriction at higher concentration was 16.55 (3.3)% and 33.11 (11.63)% in the proximal and distal segments respectively. The two different patterns of the vasomotor response coexisted in eight (53%) of the 15 patients. Intracoronary isosorbide dinitrate caused a greater increase in the coronary luminal diameter of distal segments than in proximal segments in group 1 (25.63 (5.16)% v 12.43 (3.48)%, P < 0.01) but not in group 2 (12.65 (2.53)% v 10.82 (3.33)%. Constriction and dilatation may occur in proximal and distal coronary artery segments, suggesting local areas of endothelial dysfunction, in response to acetylcholine in patients with chest pain and angiographically normal coronary arteries.

Epicardial coronary arteries are not adequately sized in hypertensive patients

This study sought to compare coronary artery dimensions in hypertensive patients and normal subjects. Myocardial oxygen demand at rest and corresponding coronary blood flow are the main determinants of large coronary artery dimensions in humans. Coronary diameters are increased in aortic valve disease. Left main, proximal and distal left anterior descending and proximal circumflex coronary artery diameters were measured by quantitative angiography in 10 control subjects (group 1) and 26 untreated hypertensive patients, 12 without (group 2a) and 14 with (group 2b) left ventricular hypertrophy. All patients had normal cholesterol levels and angiographically normal coronary arteries. Measurements were made at baseline and after 2 mg of intracoronary isosorbide dinitrate to obtain maximal dimensions of vessels. Coronary flow velocity was measured in the distal left anterior descending coronary artery by Doppler ultrasound. Despite a higher rate-pressure product in hypertensive patients, all segment diameters were slightly but not significantly higher at baseline in group 2b than in groups 1 and 2a. Diameters were similar in the three groups after isosorbide dinitrate. Conversely, coronary flow velocity was significantly higher in hypertensive patients than in group 1 either at baseline (10.4 +/- 2.2 [mean +/- SD] cm/s [group 2a] and 12.8 +/- 2.4 cm/s [group 2b] vs. 6.5 +/- 2.0 cm/s [group 1], all p < 0.001) or after isosorbide dinitrate (6.8 +/- 2.8 cm/s [group 2a] and 7.8 +/- 2.1 cm/s [group 2b] vs. 3.7 +/- 0.8 cm/s [group 1], p < 0.01 and p < 0.001, respectively). Despite an elevated myocardial oxygen demand, maximal dimensions of large coronary arteries are not increased in hypertensive patients, resulting in an elevated coronary flow velocity that may increase longitudinal shear stress at the endothelial surface. This elevated flow velocity might be an important determinant in the pathogenesis of atherosclerosis in hypertensive patients.

Influence of plasma lipoprotein(a) levels on coronary vasomotor response to acetylcholine

This study was undertaken to examine the influence of plasma lipoprotein(a) [Lp(a)] levels on coronary endothelial vasomotor function. Epidemiologic studies have demonstrated a direct relation between elevated plasma levels of Lp(a) and increased risk of coronary artery disease. Well recognized coronary risk factors are known to affect endothelium-dependent vasomotion; however, the influence of Lp(a) on coronary vasomotor function has not been determined. We used quantitative coronary angiography to measure left anterior descending coronary artery diameter changes produced by intracoronary acetylcholine and isosorbide dinitrate in 30 patients with angiographically normal coronary arteries. Plasma Lp(a) levels were determined with enzyme-linked immunosorbent assay. Vasomotor response to acetylcholine ranged from +13% to -47% in the proximal, from +23% to -53% in the middle and from +13% to -56% in the distal segment of the left anterior descending coronary artery. According to univariate linear regression analysis, Lp(a) had a significant inverse correlation with vasomotor response to acetylcholine: r = 0.47, p < 0.01 in the proximal; r = -0.61, p < 0.001 in the middle; and r = -0.52, p < 0.01 in the distal segment of the left anterior descending coronary artery. By multiple stepwise regression analysis, plasma Lp(a) was the significant predictor of vasomotion in response to acetylcholine in all tested segments (p < 0.01). Elevated Lp(a) levels were associated with impairment of endothelium-dependent vasodilation even when atherosclerotic lesions were not recognizable by angiography. This finding suggests that elevated plasma levels of Lp(a) cause endothelial dysfunction and may contribute in part to later development of atherosclerosis, as shown in epidemiologic studies.

Early Impairment of Acetylcholine-Induced Endothelium-Dependent Coronary Vasodilation Is Not Predictive of Secondary Graft Atherosclerosis

To test the hypothesis that the magnitude of early constriction of coronary arteries to acetylcholine might be a useful predictor of secondary graft atherosclerosis. The responses of epicardial coronary arteries to stepwise intracoronary infusion of acetylcholine (10(-8)M to 10(-5)M) were compared in 7 control subjects and in 18 patients who had undergone transplants within 2 months after surgery. Vessel dimensions (percent basal diameter) were measured by quantitative angiography. Follow-up at 1 year showed angiographically normal coronary arteries in 12 patients (group 1) and coronary atherosclerosis in 6 patients (group 2). In control subjects, acetylcholine induced a dose-dependent dilation from 10(-8)M to 10(-6)M. No significant variation was observed at 10(-5)M. In patients with transplants early after surgery, diameters did not vary significantly from base at 10(-8)M in either group and constricted significantly at higher concentrations. Vasodilator responses to intracoronary isosorbide dinitrate were similar in both groups with transplants early after surgery, and at 1 year in group 1, but significantly lower than in control subjects. In patients who had undergone transplants, acetylcholine-induced endothelium-dependent coronary artery dilation is similarly impaired early after surgery (within 2 months) in patients with and without coronary atherosclerosis at 1-year follow-up. Thus, response to acetylcholine is not a predictor of secondary atherosclerosis in patients with heart transplants.

Effects of continuous intravenous infusion of isosorbide dinitrate on development of tolerance to vasodilating action in human epicardial coronary arteries

This study was performed to determine the effects of long-term intravenous infusion on the coronary vasodilating actions of continuous intravenous and bolus intracoronary administration of isosorbide dinitrate (ISDN). With quantitative coronary angiography, the coronary diameter and the vasodilating response to intracoronary ISDN (1 mg) at angiographically normal segments were studied before and after intravenous administration of ISDN, 10 to 60 μg/min for 1 hour, 2 days, or 5 days. The vasodilating effects of intravenous ISDN were 72% ± 13%, 65% ± 21%, and 6% ± 11% of the response to intracoronary ISDN in the baseline study in each group. Irrespective of the duration of intravenous infusion, subsequent intracoronary ISDN dilated coronary arteries to extent similar to that observed in each baseline study. In conclusion, significant coronary vasodilating effects of intravenous ISDN were observed after a 2-day infusion, whereas tolerance to the vasodilating effects apparently developed within 5 days of infusion. The vasodilating response to bolus intracoronary ISDN was preserved even when the vasodilating effects of intravenous ISDN were no longer present.