Over the past 20 years, percutaneous transluminal coronary angioplasty (PTCA) has emerged as the treatment of choice for many patients with atherosclerotic coronary artery disease. With increased experience and technical advances, the procedural success rate has risen to about 90%. Despite dramatic improvements in technology, the incidence of restenosis within 6–12 months of successful PTCA remains 30–45%.1,2 Intracoronary stents were designed to prevent coronary restenosis after coronary angioplasty.3–5 Stents scaffold coronary arteries after angioplastic treatment and inhibit elastic recoil, resulting in a larger and more circular focal lumen.3,6–9 Apart from a greater lumen expansion, stents also lead to a smoother, fluid-dynamically more favorable vessel profile in comparison to balloon angioplasty.3 After balloon deflation, the stent maintains its expanded cylindrical configuration, forcing intraluminal irregularities against the vessel wall. Stenting results in a much greater increase in lumen diameter than achieved with balloon angioplasty alone.8 Recently, it has been demonstrated that coronary stent implantation leads to an acute and more enhanced restoration of coronary flow reserve in comparison to conventional balloon angioplasty.10 Former studies showed that abnormalities in left ventricular diastolic filling occur in patients with coronary artery disease (CAD) and precede the development of systolic dysfunction.11,12 It has not yet been clarified whether the Doppler diastolic filling abnormalities observed in patients with CAD alter immediately after successful dilatation of the lesion independently if plain balloon angioplasty or balloon angioplasty plus additional stent implantation was performed. This study sought to evaluate whether the diastolic left ventricular function correlates with the increased lumen diameter or the more enhanced restoration of the coronary flow reserve by stent implantation. Methods Patients. We recruited 194 consecutive patients (age, 57 ± 6 years; 138 men, 56 women) scheduled to undergo coronary angioplasty because of stable angina pectoris (Canadian Cardiovascular Society class II and III) due to a single lesion in a coronary artery (percent diameter stenosis > 80%). Further inclusion criteria were sinus rhythm and normal left ventricular function at rest (left ventricular ejection fraction > 55%). Exclusion criteria were diabetes mellitus; manifest arterial hypertension and hypertensive heart disease (wall thickness of left ventricle > 12 mm in the M-mode echocardiography); relevant arrhythmia-like higher-grade AV-blockings; atrial fibrillation and higher-grade ventricular extra systoles (Lown class IV); myocarditis; and inadequate echocardiographical resonance. Patients were not included in the study if they demonstrated hemodynamically relevant valvular heart disease, dilative or hypertrophic cardiomyopathy and pulmonary disease with evidence of pulmonary hypertension. Prior myocardial infarction was ruled out based on the patient´s history, electrocardiographic criteria and regional akinesia or dyskinesia of the left ventricular wall as documented by levocardiography. Oral antianginal treatment (beta-blocker, n = 168; nitrates, n = 194; calcium antagonists, n = 178) was interrupted on the day of the cardiac intervention and continued after the intervention. The decision for additional stent implantation was guided by the judgement of the interventional cardiologist based on an unsatisfactory primary result after balloon angioplasty (major dissection, hemodynamically relevant residual stenosis). Patients with conventional balloon angioplasty alone (group 1, n = 116) were compared to patients with balloon angioplasty plus adjunctive stenting (group 2, n = 78). Study protocol. Angina was classified according to the Canadian Cardiological Society angina classification.13 Prior to coronary intervention in all patients, a transthoracic echocardiography was carried out along with a standard 12-lead electrocardiogram at rest, an exercise electrocardiogram and Holter monitoring. Forty-eight hours after catheter intervention, transthoracic echocardiography, electrocardiography at rest and Holter monitoring were repeated in all patients. Resting and exercise electrocardiograms. In all patients, a standard 12-lead electrocardiogram was assessed at rest, and an exercise electrocardiogram was carried out. The bicycle ergometry protocol begins at a workload of 25 Watt and increases in 25 Watt increments every 2 minutes. Exercise is terminated if the maximum endurance frequency is reached. Criteria for early termination of exercise were ischemic ST-segment depression > 2 mm; severe fatigue or dyspnea; ventricular or supraventricular tachycardia; and a decrease in or abnormal elevation in systolic blood pressure. Holter ST monitoring. Holter ST monitoring was performed in all patients prior to the interventional procedure and 48 hours afterward. Criteria for episodes of silent ischemia were horizontal or downsloping ST-segment depression; depth of the ST segment depression > 1 mm; and duration of ST-segment depression > 1 minute. Functional capacity. In order to objectify the functional work capacity, the results of the symptom limited ergometric exertion on the bicycle ergometer were taken as a basis. The exercise workloads were expressed in metabolic equivalents (MET). (1 MET = 3.5 ml/kg/minute O2).14 Echocardiographic examination. M-mode, two-dimensional and pulsed-wave Doppler echocardiographic examinations were performed in the resting state with a Toshiba SSH 160A ultrasound imager, using a 2.5 MHz transducer by a single observer trained in Doppler echocardiography, who was blinded in respect to the patient clinical data as well as to the revascularization procedure chosen (balloon angioplasty alone or balloon angioplasty plus stent implantation). All examinations were recorded on videotape and calculations were made directly on the videoscreen. M-mode echocardiographic recordings were obtained and measurements of left atrial and left ventricular dimensions and left ventricular wall thickness were made according to the recommendations of the American Society of Echocardiography. In addition, left ventricular systolic fractional shortening and left ventricular muscle mass15 were calculated. Mitral inflow velocities were measured at the level of the leaflet tips in the standard 4-chamber view to measure various parameters of left ventricular diastolic function like early and late maximal filling velocities, isovolumetric relaxation, acceleration and deceleration times. The velocity of the pulmonary vein flow was documented by placing the PW “sample volume” in apical 4-chamber view at the opening of the right upper pulmonary vein beside the atrium septum, and by measuring it at the end of the expiration. The results of 5 consecutive cardiac cycles were averaged during the measurements.16–18 Cardiac catheterization. Cardiac catheterization was performed according to standard clinical practice by the femoral approach using 7 French sheaths. At least 6 standardized projections of the left coronary artery and 2 projections of the right coronary artery were obtained. Coronary arteriography was also performed in orthogonal views selected to best demonstrate the target lesion. Coronary balloon angioplasty was performed using appropriately sized balloon catheters ranging in diameter from 2.5–4.5 mm. Stent diameters varied between 2.5–4.5 mm, while stent length ranged from 9–16 mm (10 ACS Multi-Link stents, Guidant Corporation, Temecula, California; 6 SITO stents, SITOmed GmbH, Unterschleißheim, Germany). The choice of procedural variables like balloon size, number of inflations, etc., was guided by the judgement of the operating interventional cardiologist. During the procedure, patients received an initial bolus injection of heparin (10,000–15,000 units) supplemented as needed to maintain an activated clotting time of > 300 seconds. The arterial sheath was removed 4 hours post procedure. All patients received aspirin 100 mg daily. Patients who underwent stent implantation received 250 mg of ticlopidine twice daily adjunctive to the aspirin medication starting on the day of intervention for 3 months. Quantitative coronary angiography. Quantitative coronary angiographic analyses were performed. The respective film excerpt showing the coronary stenosis was digitized by means of a high-resolving video camera, and enlarged 2.6-fold. The vessel contours were automatically determined along the vessel middle line. The absolute stenosis minimal lumen diameter (MLD) and reference diameter were measured online by the computer using the known contrast-empty guiding catheter as a scaling device. Acute gain was defined as the difference between the MLD immediately after the procedure (balloon angioplasty or balloon angioplasty plus additional stent implantation) and the MLD before the procedure. The stenosis grade of the coronary arteries was determined by means of the diameter-method: (1-diameter at the stenosis/pre-stenotic diameter) x 100. Angiographic success was defined as diameter improvement > 20% with a residual stenosis Statistics. The statistical evaluations were carried out with a statistical software program [Statistical Package for Social Sciences (SPSS) for Windows; SPSS, München, Germany]. The data were specified as mean values with standard deviations. In order to compare the groups, the “Kruskal-Wallis” test was applied as “one-way ANOVA” test. The Mann-Whitney U-Test was used for comparisons between 2 groups, while the Wilcox signed rank test was used for intragroup comparisons. Non-continuous data were evaluated with Fisher’s exact test. Correlation coefficients were generated with the Spearman test. A significant group difference between groups was assumed at a level of error of Patients. A total of 194 patients were enrolled. Baseline patient characteristics are shown in Table 1. The clinical characteristics and prevalence of coronary risk factors were similar between the 2 groups (Table 1). All patients in both groups reported angina during regular daily activities and each group demonstrated significant ST-segment depression at rest and during ergometric exercise testing, which was mainly stopped for physical exhaustion at a moderate level of exercise. Cardiac catheterization, angioplasty and quantitative coronary angiography. According to the entry criteria of the study, all patients demonstrated coronary single-vessel disease and normal left ventricular function at rest (Table 2). Target lesions were predominantly located in the left anterior descending artery in both groups (group 1: 53% versus group 2: 56%; p = NS) and eccentric and distal stenoses were evenly distributed. The average reference diameter in the target vessel (3.33 ± 0.25 mm versus 3.29 ± 0.23 mm; p = NS); the minimal lumen diameter (0.56 ± 0.1 mm versus 0.53 ± 0.11 mm; p = NS), the total inflation time (84 ± 12 seconds versus 86 ± 17 seconds; p = NS) and the maximal pressure (14 ± 2 atm versus 14 ± 3 atm; p = NS) were comparable in both groups (Table 2). The immediate results after the procedure, as assessed by quantitative angiography, are also summarized in Table 2. Angiographic and clinical success was achieved in all patients. An unsatisfactory primary result after plain balloon angioplasty (major dissection, hemodynamically relevant residual stenosis) indicated adjunctive stenting in 78 patients. After catheter intervention, patients with balloon angioplasty and stent implantation had a significantly greater minimal luminal diameter (2.58 ± 0.28 mm versus 2.36 ± 0.20 mm; p Holter monitoring. In order to detect spontaneous silent ischemia, Holter monitoring was performed in all patients prior to intervention and 48 hours after intervention. Prior to intervention, spontaneous silent ischemia was documented in 61% of the patients (n = 116). Both groups were comparable concerning the episodes/24 hours and the number of patients in whom ST-segment depression was detected. After intervention, a relevant discrepancy between the 2 patient collectives was demonstrated. In both collectives, an improvement could be shown with a significantly reduced number of patients who experience episodes of silent ischemia, but the episodes with ST-segment depression were significantly reduced 48 hours after the procedure in only group 2 (Table 3). Morphological and hemodynamic results. No differences were found in heart rate and blood pressure at the time of the 2 Doppler examinations (Table 4). There was no significant difference regarding the morphological parameters evaluated by echocardiography (Table 5). The echocardiographic results for the left atrial dimensions and for the width of the aorta ascendens did not reveal any relevant differences between the 2 collectives. Both groups showed a comparable systolic function at rest as indicated by the amount of fractional shortening (fractional shortening, 36 ± 4% for group 1 versus 35 ± 5% for group 2; p = NS). Left ventricular muscle mass was within normal range in both collectives (220 ± 15 g in group 1 versus 210 ± 21 g in group 2; p = NS) (Table 5). The interventional procedure had no influence on the morphological and hemodynamic parameters (Tables 4 and 5). Doppler echocardiography results. The initial Doppler echocardiography examination documented a left ventricular diastolic dysfunction in the sense of disturbed relaxation in all patients with a decrease of the early diastolic filling (VE, 0.52 ± 0.07 m/s), compensatory increase of the atrial filling component (VA, 0.61 ± 0.08 m/s), with lengthened deceleration time (DT, 258 ± 14 ms) and isovolumetric relaxation time (IVRT, 126 ± 11 ms). There was no significant difference between the 2 patient collectives concerning the Doppler echocardiographically evaluated parameters of left ventricular diastolic function (Table 6). The pulmonary vein flow velocities and the durations of the atrial wave were within the normal range in all patients. Thereby, changes in the loading conditions could be excluded (Table 6). Forty-eight hours after cardiac intervention, a significant improvement of the left ventricular diastolic parameters could be documented in patients who were treated with balloon angioplasty and adjunctive stenting. After sole balloon angioplasty, only a change in direction without normalization (age corresponding) of the left ventricular diastolic functional parameters could be registered (Table 6). There were no relevant differences concerning the electrocardiographic, echocardiographic or angiographic results between patients with left anterior descending, right circumflex and right coronary artery vessel disease in both groups. Discussion The data presented demonstrate that all patients with CAD have an abnormal pattern of left ventricular diastolic filling in the sense of a disturbed relaxation detectable by mitral valve Doppler examination. Radionuclide angiographic studies already showed that abnormalities in left ventricular diastolic filling occur in patients with CAD and often precede the development of systolic dysfunction.19–21 A characteristic ischemic cascade could be described in an animal experiment with pathophysiological mechanisms in a defined temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia.22 Flow inhomogeneities between subendocardial and subepicardial layers are first signs of ischemia, directly followed by metabolic changes and afterward disturbed left ventricular diastolic function. Only later do regional and global systolic dysfunctions appear, following electrographic changes. Angina pectoris is documented last. The Doppler echocardiographically determined data in this study confirm this pathophysiologically-based hierarchy of hemodynamic changes with ischemia-induced left ventricular dysfunction. Former studies documented that Doppler echocardiography provides a useful noninvasive technique for assessment of left ventricular diastolic filling in patients with CAD.23–25 Doppler diastolic filling indexes have correlated closely with those measured from cineangiography25 and radionuclide angiography.23 Our data demonstrate that balloon angioplasty and additional stenting result in a statistically relevant improvement of parameters of left ventricular diastolic function within 48 hours following the elective procedure. After plain balloon angioplasty, only a change in direction without normalization of the left ventricular diastolic functional parameters could be registered. The immediate hemodynamic improvement following stent implantation has to be attributed to a more pronounced antiischemic effect in comparison to plain balloon angioplasty. Influences on morphological and functional vascular properties of the epicardial conduction vessels as well as on the coronary microcirculation have to be regarded as potential mechanisms for enhanced perfusion. Stent implantation leads to a significantly increased acute luminal gain and hence less severe residual stenosis in comparison to conventional balloon angioplasty immediately after the procedure.3,8 This could be confirmed by the data our study presented. Although the degree of residual stenosis was lower in the patient group with additional stent implantation, a residual stenosis of 28% post balloon angioplasty alone is considered to be an angiographic success. Therefore, it seems unlikely that the angiographically defined degree of residual obstruction is the decisive factor for the left ventricular diastolic improvement following the adjunctive coronary stenting. The angiographically defined degree of coronary obstructions is not associated with depressed coronary blood flow at rest as well as during exercise.26 However, it cannot be ruled out that nonocclusive clots and elastic recoil lead to hemodynamically relevant morphological obstruction, since these phenomena occur within the early hours following coronary angioplasty.5,27 Stents scaffold coronary arteries after angioplastic treatment and inhibit elastic recoil, resulting in a larger and more circular focal lumen.9,10 These locally improved flow conditions cause extensive normalization of the coronary vasodilatative flow reserve and myocardial perfusion reserve in comparison to plain coronary angioplasty.1,3 Adjunctive coronary stent implantation normalized poststenotic myocardial perfusion immediately in contrast to balloon angioplasty alone, resulting from a larger postprocedural lumen and a more pronounced inhibition of elastic recoil.10 Several mechanisms could be responsible for the inadequate normalization of the vasodilatory flow reserve after plain coronary angioplasty, e.g., increased basal flow during transient ischemia, microvascular stunning after circumscribed coronary embolization or inadequate vasodilatory capability to regulate coronary microcirculation. Nevertheless, a coronary stenosis grade lower than 30% after balloon angioplasty alone can hardly explain the merely insignificant improvement of the left ventricular diastolic functional parameters 48 hours after cardiac intervention. Since the left ventricular diastolic functional parameters are assessed as sensitive signs of ischemia, it must be postulated that, despite angiographically successful balloon angioplasty, a reduced coronary flow5 due to intravasal clots, elastic recoil, initial macroscopically unrecognizable dissections with endothelial flaps as well as a dynamic tendency towards restenosis leads to a hemodynamically relevant but angiographically not clearly visible morphological obstruction during the first hours after balloon dilatation.6,28,29 Finally, the angiographic sensitivity for the recognition of nonocclusive coronary thrombi is low.8,30 Furthermore, interventionally-induced vascular lesions withdraw physiological vascular relaxing qualities from the vessel wall.5 In an experimental setting, an increase of the cyclic coronary vascular wall contractions could be documented after mechanical vessel injuries. Nonocclusive thrombi induce local vasoconstrictions, which occur in up to 90% of cases with endothelial lesions.27 These local vasoconstrictions lead to region accumulation and further distribution of potentially vasoconstrictive substances like thrombin, serotonin and endothelin despite optimal antithrombotic therapy.27,31,32 The alpha-adrenergic vasoconstriction accentuates the compromised vascular lumen following balloon angioplasty.7 Thus, angiographically documented vasoconstrictions appear 4 hours after balloon angioplasty in the dilated vessel segment as well as in the distally situated epicardial segments.8,33 Eight days after intervention, these vasoconstrictions were no longer angiographically detectable.8,34 These local vasoconstrictions can be interpreted as intermittent myocardial ischemia. Therefore, additional stent implantation leads not only to a more enlarged vascular lumen than balloon angioplasty alone, but also omits local vasoconstrictions. Apart from the scaffolding effect of stents, which prevents elastic recoil and vasoconstriction, enhanced flow-mediated release of vasorelaxing nitric oxide has to be regarded as a further vascular mechanism for enhanced perfusion.35 Persisting diastolic dysfunction following balloon angioplasty reflects repetitive spontaneous ischemic episodes with the persistence of pathological alterations of myocardial relaxation and contractile properties despite restored blood flow. The statistically relevant improvement of the left ventricular diastolic functional parameters after adjuvant stent implantation 48 hours after successful intervention can be interpreted as a sensitive, non-invasive indirect marker of an improved coronary perfusion. The higher evidence of spontaneous ischemia during Holter monitoring in patients after plain angioplasty compared to patients in group 2 supports the hypothesis that endothelial disruption caused by plain balloon angioplasty causes nonocclusive thrombi and/or focal coronary spasm, since this mechanism should not take place in patients treated with stents due to the stents’ scaffolding properties. Another study that evaluated the occurrence of ischemic episodes as documented by ST Holter analyses before and after primarily successful coronary balloon angioplasty also showed a marked reduction of the ischemic episodes.36 Because it is difficult to tell if changes in left ventricular filling velocities depend on changes in relaxation induced by ischemia or merely in the loading conditions, pulmonary vein flow velocities were documented in all patients. The pulmonary vein flow velocities demonstrated comparable loading conditions in both groups and pseudonormalization 48 hours after balloon angioplasty plus adjunctive stenting in group 2 can be excluded. Based upon the data of this study, primary stenting should be considered in all patients with single obstructive coronary disease. Since the determination of the left ventricular diastolic functional parameters must be assessed as prematurely sensitive, noninvasive parameters of myocardial ischemia, it should be clarified whether determination of the left ventricular diastolic functional parameters makes a prediction regarding restenosis after successful coronary intervention. Conclusion. Additional stenting leads to a swifter improvement of left ventricular diastolic function in comparison to plain balloon angioplasty within 48 hours following the procedure. This has to be attributed to an increased immediate antiischemic therapeutic effect of the scaffolding properties of stents, which are likely to inhibit local intermittent coronary vasoconstriction at the site of the intervention. Future studies will have to determine whether stent implantation results in improved contractility and salvaged myocardium during immediate revascularization in the setting of acute myocardial infarction. Given the comparably low rate of restenosis following stent implantation and the known predictive value of angiographic and functional signs of early luminal loss, it remains to be determined whether assessment of diastolic function allows for prediction of late restenosis.
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