Heinrich Wieneke

Plaque Distribution and Vascular Remodeling of Ruptured and Nonruptured Coronary Plaques in the Same Vessel: An Intravascular Ultrasound Study In Vivo

OBJECTIVES This study was designed to identify potential differences between the intravascular ultrasound (IVUS) characteristics of spontaneously ruptured and nonruptured coronary plaques. BACKGROUND The identification of vulnerable plaques in vivo may allow targeted prevention of acute coronary events and more effective evaluation of novel therapeutic approaches. METHODS Intravascular ultrasound was used to identify 29 ruptured plaques in arteries containing another nonruptured plaque in an adjacent segment. Intravascular ultrasound characteristics of these plaques were compared with plaques of computer-matched controls without evidence of plaque rupture. Plaque distribution was assessed by measuring the eccentricity of lumen location (inside the total vessel). Lumen cross-sectional area narrowing was calculated as [1 - (target/reference lumen area)] x 100%. A remodeling index was calculated as lesion/reference arterial area (>1.05 = compensatory enlargement, <0.95 = shrinkage). RESULTS Among the three groups of plaques, there was no significant difference in quantitative angiographic parameters, IVUS reference dimensions and IVUS lumen cross-sectional area narrowing. There was a difference in plaque distribution; lumen location by IVUS was significantly more eccentric in ruptured than in nonruptured (p = 0.002) and control plaques (p < 0.0001). The arc of disease-free vessel wall was larger in ruptured than in control plaques (p < 0.0001). The remodeling pattern of ruptured and nonruptured plaques differed significantly from that of the control plaques (p = 0.0001 and 0.003); compensatory enlargement was found in 66%, 48%, and 17%, whereas shrinkage was found in 7%, 10% and 48%, respectively. CONCLUSIONS Intravascular ultrasound assessment of plaque distribution and vascular remodeling may help to classify plaques with the highest probability of spontaneous rupture.

Relationship Between Cardiovascular Risk as Predicted by Established Risk Scores Versus Plaque Progression as Measured by Serial Intravascular Ultrasound in Left Main Coronary Arteries

Background—Intravascular ultrasound (IVUS) is increasingly used as an end point in studies aimed at reducing progression or inducing regression of coronary artery disease. However, data linking serial changes by IVUS with clinical outcomes are scarce. Methods and Results—In the absence of a validated risk score for secondary prevention, we compared 3 established risk scores for primary prevention—PROCAM, SCORE, and Framingham—with plaque progression and lumen reduction as assessed with serial IVUS (follow-up, 18±9 months) in atherosclerotic left main coronary arteries of 56 patients with established atherosclerosis. For all 3 algorithms, patients at highest estimated risk of events showed greater plaque progression than patients at lowest risk (P<0.05 to <0.01). There were positive linear relationships between the risk of clinical events and plaque progression (r=0.41 to 0.60; P<0.002 to <0.0001). This translated into a greater decrease in lumen dimensions with increasing risk (P<0.05, PROCAM and SCORE). Risk prediction using the PROCAM algorithm showed the strongest relation with serial IVUS. During follow-up, 18 patients suffered from adverse cardiovascular events; these patients had an annual plaque progression that was significantly greater than other patients (25.2±19.4% versus 5.9±15.6%, P<0.001). Conclusions—There was a positive linear relationship between the estimated risk of clinical events derived from all 3 established risk-score algorithms and the extent of plaque progression measured by serial IVUS. This translated into stenosis progression (reduction in lumen dimensions) with increasing clinical risk.

Synergistic effects of a novel nanoporous stent coating and tacrolimus on intima proliferation in rabbits

To overcome the problem of in‐stent restenosis, the concept of local delivery of antiproliferative or immunosuppressive drugs has been introduced into interventional cardiology. Local drug delivery can be achieved by drug‐eluting stents coated with polymer surfaces used for controlled drug release. However, several polymer coatings have shown an induction of inflammatory response and increased neointima formation. In the present study, the effect of a new inorganic ceramic nanoporous aluminum oxide (Al2O3) coating on neointima proliferation and its suitability as a carrier for the immunosuppressive drug tacrolimus have been investigated. 316 L stainless steel coronary stents were coated with a 500 nm thin nanoporous aluminum oxide layer. This ceramic nanolayer was used as a carrier for tacrolimus. Bare stents (n = 6), ceramic coated stents (n = 6), and ceramic coated stents loaded with 60 (n = 7) and 120 μg (n = 6) tacrolimus were implanted in the common carotid artery of New Zealand rabbits. The ceramic coating caused no significant reduction of neointimal thickness after 28 days. Loading the ceramic stents with tacrolimus led to a significant reduction of neointima thickness by 52% for 60 μg (P = 0.047) and 56% for 120 μg (P = 0.036) as compared to the bare stents. The ceramic coating alone as well as in combination with tacrolimus led to a reduced infiltration of lymphocytes and macrophages in the intima in response to stent implantation. Ceramic coating of coronary stents with a nanoporous layer of aluminum oxide in combination with tacrolimus resulted in a significant reduction in neointima formation and inflammatory response. The synergistic effects of the ceramic coating and tacrolimus suggest that this new approach may have a high potential to translate into clinical benefit. Catheter Cardiovasc Interv 2003;60:399–407.

Abnormal Coronary Flow Velocity Reserve After Coronary Intervention Is Associated With Cardiac Marker Elevation

Background—Residual reduction of relative coronary flow velocity reserve (rCVR) after successful coronary intervention has been related to microvascular impairment. However, the incidence of cardiac enzyme elevation as a surrogate marker of an underlying embolic myocardial injury in these cases has not been studied. Methods and Results—A series of 55 consecutive patients with successful coronary stenting, periprocedural intracoronary Doppler analysis, and determination of creatine kinase (CK; upper limit of normal [ULN] for women 70 IU/L, for men 80 IU/L) and cardiac troponin T (cTnT; bedside test, threshold 0.1 ng/mL) before and 6, 12, and 24 hours after intervention were studied. Postprocedural rCVR was the only intracoronary Doppler parameter that independently correlated with cTnT (r =−0.498, P <0.001) and CK outcome (r =−0.406, P =0.002). Receiver operating characteristic analysis identified a postprocedural rCVR of 0.78 as the best discriminating value, with a sensitivity of 83.3% and 69.2% and a specificity of 79.1% and 76.2% for detection of cTnT and CK elevation, respectively. Stratified according to this cutoff value, the incidence of cTnT elevation was 52.6% in patients with (n=19) and 5.6% in patients without (n=36) a postprocedural rCVR <0.78 (P <0.001), associated with a CK elevation >1 times the ULN in 36.8% and 5.6% (P =0.005) of patients, respectively. Conclusions—Cardiac marker elevation can frequently be found after coronary procedures that are associated with a persistent reduction of rCVR, indicating procedural embolization of atherothrombotic debris with microvascular impairment and myocardial injury as a potential underlying mechanism.

Stent Coating: A New Approach in Interventional Cardiology

Background: Since its introduction in clinical cardiology, several studies have shown the superiority of coronary stent implantation as compared to conventional angioplasty. However, restenosis still remains a major drawback of this new technique. Basic research in animal models could identify stent-related factors like stent-material and stent-design as major determinants of intima proliferation. Since materials with good biocompatibility often have unsuitable mechanical properties and vice versa, the concept of stent coating has been developed to allow the combination of favorable characteristics from different materials. Passive Coating: In general, passive coatings, which only serve as a barrier between the stainless steel and the tissue, and active coatings, which directly interfere with the process of intima proliferation have been identified. Currently there are several passive coatings commercially available with good results in animal models and preliminary reports from clinical studies. Acitve Coating: As any surface induces some kind of tissue reaction promoting restenosis, an active stent coating with antiproliferative drugs has been proposed. However, while animal studies revealed convincing results, preliminary clinical studies not only showed active stent coating effective in preventing restenosis, but also demonstrated the potential risks of this new approach. Although this technique may harbor some specific risks, with the introduction of stent coating a new chapter of interventional cardiology has been flipped open.Hintergrund: Verschiedene Studien konnten eine Überlegenheit der Stentimplantation gegenüber der alleinigen koronaren Angioplastie belegen. Dennoch bleibt die Restenose ein gravierendes Problem der interventionellen Kardiologie. Bei den zur Restenose disponierenden Faktoren können Patientenfaktoren, wie Diabetes mellitus und Stenosemorphologie, von Stentfaktoren, wie Stentmaterial und -design, unterschieden werden. Passivbeschichtung: In dem Bemühen, die Restenoserate zu senken, ist daher das Konzept der Stentbeschichtung entwickelt worden. Durch dieses Vorgehen lassen sich biokompatible Eigenschaften eines Beschichtungsmaterials mit den guten mechanischen Eigenschaften eines Trägermaterials verbinden. Darüber hinaus erlaubt die Beschichtung koronarer Stents die Bindung von antiproliferativ und antiinflammatorisch wirkenden Substanzen an die Stentoberfläche. Dient die Beschichtung demzufolge lediglich zu einer Verbesserung der Biokompatibilität, bezeichnet man diese auch als Passivbeschichtung. Soll hingegen durch das Aufbringen eines Medikaments direkt die Intimabildung unterdrückt werden, handelt es sich um eine Aktivbeschichtung. Aktivbeschichtung: In den letzten Jahren sind verschiedene Passiv- und Aktivbeschichtungen tierexperimentell und klinisch untersucht worden. Dabei hat sich gezeigt, dass insbesondere die Aktivbeschichtungen ein hohes Potential zur Prävention der Restenose besitzen. Als Medikamente kommen Substanzen wie Sirolimus und Tacrolimus zur Anwendung, die ein vorwiegend immunsuppressives Wirkspektrum aufweisen und in der Transplantationsmedizin eingesetzt werden. Daneben werden jedoch auch Substanzen wie Paclitaxel verwendet, die aus der Tumortherapie bekannt sind. Neben viel versprechenden klinischen Ergebnissen sind jedoch auch erste Risiken dieser neuen Technologie aufgezeigt worden. So zeigen Untersuchungen, dass eine Polymerbindung von Medikamenten zu entzündlichen Reaktionen führen kann. Geht dann die Wirkung des Medikaments zurück, überwiegt die Inflammation und ein lediglich zeitlich versetzter Restenoseprozess beginnt. Auch wenn diese Komplikationen die initiale Euphorie gedämpft haben, stellt die Beschichtung koronarer Stents einen Meilenstein in der Bekämpfung der Restenose dar.

Corrected coronary flow velocity reserve: a new concept for assessing coronary perfusion☆

OBJECTIVES In order to limit the variability of coronary flow velocity reserve (CFVR), we analyzed which factors independently affect CFVR and established a new parameter integrating these factors. BACKGROUND Coronary flow velocity reserve (CFVR) is a frequently used parameter for evaluating the physiological significance of epicardial stenosis and microvascular function. Since CFVR measurements are done in substantially different hemodynamic and clinical situations, interpretation of CFVR requires correction for major influencing factors. METHODS In 141 patients with angina-like symptoms and angiographically unobstructed coronary arteries, intracoronary Doppler measurements were performed in at least two coronary vessels. Coronary flow velocity reserve was calculated as the ratio of hyperemic average peak velocity (hAPV), after intracoronary bolus of adenosine, to baseline average peak velocity (bAPV). RESULTS Analysis of covariance revealed that only bAPV (p < 0.0001) and age (p < 0.0001) were independent factors influencing CFVR. Based on a regression model for estimation of predicted CFVR values, individual CFVR values (CFVRind) obtained at different bAPV and age were transformed in corrected CFVR values (CFVRcorr) by relating them to a mean bAPV of 15 cm/s and a mean age of 55 years. The transformation from CFVRind into CFVRcorr for the left anterior descending artery can be done by using the following equation: CFVRcorr = 2.85*CFVR(ind)*10(0.48*log(bAPV)+(0.0025*age)-1.16). When applying this new parameter to conditions assumed to cause microvascular dysfunction, analysis showed that only patients with diabetes showed a significant decrease of traditional CFVR and CFVRcorr, whereas a history of hypertension and current smoking habit had no influence on CFVRcorr. CONCLUSIONS The concept of CFVRcorr standardizes CFVR for bAPV and age as the major physiological determinants. Especially in patients with microvascular dysfunction, this approach may help to discriminate between conditions directly affecting vasodilator reserve and conditions primarily affecting bAPV.

Early clinical experience with the implantation of a novel synthetic coronary stent graft.

Coating stents with autologous venous grafts has been suggested to prevent problems associated with conventional stenting, but the need for surgical vessel harvest hampered broad application. A novel synthetic coronary stent graft (CSG) overcomes this limitation by a synthetic membrane, fixed between two thin metallic stents. We successfully implanted 21 CSGs in 18 patients for treatment of acute coronary rupture, thrombus‐containing lesions, and lesions with plaque rupture or adjacent pseudoaneurysm. Substantial residual angiographic diameter stenoses were seen in seven CSGs (25% ± 10% vs. 8% ± 6%; P < 0.01), which were implanted with relatively small balloon catheters (balloon‐to‐artery ratio 1.00 ± 0.09 vs. 1.24 ± 0.18; P = 0.01) and required postdilatation. Overall, the largest balloon catheter applied measured 4.0 ± 0.7 mm (balloon‐to‐artery ratio 1.21 ± 0.20) and the inflation pressure was 16 ± 3 atm. Final intravascular ultrasound imaging demonstrated adequate and symmetrical expansion of the CSG (≥85% ± 15% of the reference lumen). Elective implantation was associated with two small non–Q‐wave myocardial infarctions, resulting from unavoidable occlusions of side branches. Thus, implantation of CSG is feasible and safe. Adequate expansion can be achieved by the use of relatively large low‐compliant balloon catheters inflated with high pressure. Cathet. Cardiovasc. Intervent. 47:496–503, 1999.

Late Enhancement: A New Feature in MRI of Arrhythmogenic Right Ventricular Cardiomyopathy?

Aim of the study was to evaluate whether late enhancement (LE) in contrast-enhanced MRI can be used to characterize fibrofatty myocardial replacement in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC). Fifteen patients with suspected ARVC underwent CE-MRI using a 1.5 T scanner. Long and short axis SSFP cine images and T1-weighted fast spin echo images were collected in all patients. After injection of 0.2 mmol/kg Gd-DTPA (Magnevist, Schering, Berlin, Germany), inversion recovery gradient echo images were acquired in long and contiguous short axes to detect myocardial LE indicating areas of fibrous tissue within the myocardium. For definition of ARVC, the ESC Task force criteria were used. In 7 (47%) of 15 patients, ARVC was diagnosed based on the ESC criteria. In all of these 7 patients, MRI showed morphologic or functional criteria of ARVC according to the ESC. LE of the right ventricular myocardium was detected in 5 (71%) of the 7 ARVC patients, additional LE of the left ventricular myocardium in 2 of these patients. None of the 7 patients meeting the ARVC diagnostic criteria had fatty RV infiltration demonstrable by conventional T1-weighted imaging. Eight patients neither showed morphologic criteria of ARVC nor LE. In conclusion, late enhancement can be detected in the right and left ventricular myocardium in some ARVC patients. LE might represent intramyocardial areas of fibrous tissue.

Non-invasive characterization of cardiac microvascular disease by nuclear medicine using single-photon emission tomography.

In about 10 to 30% of patients with typical angina undergoing coronary angiography for suspicion of stenotic coronary artery disease angiographically normal coronary arteries are found. Kemp et al. in 1973 coined the term syndrome X to describe this entity. In a substantial portion of these patients pathologic findings in myocardial scintigraphy are present.Sensitivity and specificity of thallium-201 exercise imaging by visual analysis of images in the presence of significant coronary stenosis is 84 and 88%, respectively. Several investigators have reported abnormal results in radionuclide exercise tests in patients with angiographically normal coronary arteries. Some of these results can be explained by myocardial bridging, vasospasm, left or right bundle branch block, hypertrophic cardiomyopathy, or absorption artifacts. In the majority of cases, however, these abnormalities are not sufficient to explain the scintigraphic findings. Formerly often claimed “false positive”, recent studies suggest that endothelial dysfunction might be the reason for the observed perfusion defects. When comparing patients with angiographically unobstructed coronary arteries with and without perfusion defects in stress myocardial perfusion imaging, patients with pathological results show a significantly lower increase of coronary flow after intracoronary injection of the endothelialdependent vasodilator acetylcholine. Endothelial-independent vasodilation, however, is not impaired in these patients. In addition, intracoronary Doppler measurements reveal that perfusion defects in myocardial scintigraphy only occur if coronary blood flow in this perfusion area is significantly reduced. These results suggest that regional endothelial dysfunction may cause hypoperfusion in myocardial perfusion imaging and underline the important role of the microcirculation in the distribution of radiotracers.Another striking scintigraphic pattern in patients with microvascular angina is the high incidence of reverse redistribution. These perfusion defects, apparent in images obtained 4 hours after exercise stress testing, often cannot be assigned to the perfusion territory of one of the major epicardial vessels. This results in a marked inhomogeneous radionuclide distribution pattern in resting images. The inhomogeneity is associated with a significant reduced resting coronary flow velocity in these patients. As histologically confirmed microvessel disease is often accompanied by slow-flow phenomenon reflecting decreased resting flow velocity, the results suggest that the inhomogeneous perfusion pattern is caused by microvascular dysfunction. Furthermore, the heterogeneity of nuclide distribution supports the hypothesis that endothelial function is not homogeneous in the entire myocardial microcirculation, but varies considerably.In conclusion, microvascular dysfunction by itself seems to cause regional myocardial hypoperfusion, as documented by myocardial scintigraphy. When interpreting pathological scintigraphic results in patients without significant epicardial stenosis, true blood flow and myocardial perfusion abnormalities must be assumed.ZusammenfassungIn der diagnostischen Koronarangiographie zeigen 10 bis 30% der untersuchten Patienten mit typischer pektanginöser Beschwerdesymptomatik nichtstenosierte Koronararterien. Bei einem großen Anteil der Patienten läßt sich in der Myokardszintigraphie jedoch ein pathologischer Befund erheben. Kemp hat 1973 für die Entität aus angiographisch normalen epikardialen Gefäßen, Angina pectoris und positivem Ischämienachweis den Begriff Syndrom X geprägt.Die Myokardszintigraphie stellt ein weit verbreitetes und gut validiertes Verfahren in der Funktionsdiagnostik der koronaren Herzerkrankung dar. Die Sensitivität und Spezifität der [201Tl] Thalliumchlorid-Szintigraphie im Hinblick auf eine signifikante epikardiale Stenose werden in Abhängigkeit von der Untersuchungstechnik mit 84 und 88% angegeben. Minderanreicherungen können außer durch höhergradige Stenosierungen der Koronargefäße bei Muskelbrücken, Koronarspasmen, beim Links- und Rechtsschenkelblock auftreten, aber auch aufgrund von Absorptionsartefakten vorgetäuscht werden. Werden oben genannte Ursachen für Perfusionsdefekte ausgeschlossen, so lassen sich dennoch bei Patienten mit Angina pectoris häufig pathologische Befunde erheben. Während Perfusionsdefekte in der Myokardszintigraphie bei Patienten mit angiographisch unauffälligen Koronararterien zunächst als „falsch positiv” gewertet wurden, deuten neuere Studienergebnisse darauf hin, daß diesen szintigraphischen Minderbelegungen eine endotheliale Dysfunktion der myokardialen Mikrozirkulation ursächlich zugrunde liegt. Werden Patienten mit angiographisch nicht stenosierten Koronararterien mit und ohne Perfusionsdefekte unter Belastung in der201TlCl-Myokardszintigraphie verglichen, so weisen Patienten mit pathologischem Belastungsszintigramm einen signifikant geringeren Anstieg des koronaren Flusses auf die Gabe des endothelabhängigen Vasodilatators Acetylcholin auf. Die endothelunabhängige Vasodilatation auf Papaverin ist hingegen in beiden Gruppen gleich. Wie intrakoronare Doppler-Messungen zeigen konnten, treten regionale Perfusionsdefekte in der Myokardszintigraphie nur dann auf, wenn ein signifikant reduzierter relativer Blutfluß in dem jeweiligen Myokardareal besteht. Diese Ergebnisse unterstreichen die wichtige Rolle der Mikrozirkulation für die Nuklidverteilung in der Myokardszintigraphie. Neben belastungsinduzierten regionalen Minderperfusionen zeigen Patienten mit nichtstenosierten Koronararterien und Angina pectoris häufig auch eine inhomogene Nuklidverteilung in Ruhe, welche unter Belastung nicht besteht. Dieses Phänomen tritt meist unabhängig vom Versorgungsgebiet der großen epikardialen Gefäße auf. Intrakoronare Doppler-Messungen zeigten, daß dieses inhomogene Verteilungsmuster mit einer reduzierten koronaren Flußgeschwindigkeit in den epikardialen Gefäßen einhergeht. Ähnliche Ergebnisse wurden in einem Kollektiv von herztransplantierten Patienten erhoben, die eine progressive Inhomogenität des Nuklidverteilungsmusters in der201TlCl-Myokardszintigraphie in Abhängigkeit von der Dauer nach Transplantation aufwiesen. Da weder angiographisch noch im intravaskulären Ultraschall signifikante Stenosierungen gefunden wurden, wird hier eine Störung der Mikrozirkulation im Rahmen einer Transplantatvaskulopathie als Ursache diskutiert.Zusammenfassend kann daher festgestellt werden, daß pathologische Ergebnisse in der Myokardszintigraphie bei Patienten mit angiographisch nichtstenosierten epikardialen Gefäßen real existierende Minderperfusionen widerspiegein. Nach den vorliegenden Untersuchungen sind diese durch regional begrenzte Störungen der myokardialen Mikrozirkulation bedingt. Ein Charakteristikum dieser durch eine Störung der Mikrozirkulation bedingten Perfusionsmuster scheint eine inhomogene Nuklidverteilung in den Redistributionsaufnahmen zu sein.

Size of emptied plaque cavity following spontaneous rupture is related to coronary dimensions, not to the degree of lumen narrowing. A study with intravascular ultrasound in vivo

OBJECTIVE To identify any potential relations between the size of an emptied plaque cavity and the remodelling pattern, plaque or vessel dimensions, lumen narrowing, and other ultrasonic lesion characteristics. DESIGN Intravascular ultrasound was used to examine prospectively 51 ruptured ulcerated coronary plaques. Cross sectional area measurements comprised lumen, vessel, plaque, and emptied plaque cavity. Lumen narrowing was calculated as 1 − (lesion lumen area/reference lumen area) × 100%. A remodelling index was calculated as lesion vessel area/reference vessel area, and plaques were divided into those with values > 1.05 (group A) and ⩽ 1.05 (group B). RESULTS Of the total of 51 plaques, 36 (71%) were assigned to group A and 15 (29%) to group B. In neither group was there a significant difference in reference dimensions and lumen narrowing. However, lesion vessel (mean (SD): 22.6 (8.1) mm2 v 17.5 (4.3) mm2; p = 0.006) and plaque areas (15.8 (6.2) mm2 v 12.8 (3.2) mm2; p = 0.03) were greater in group A than in group B. The cavity inside the plaque was larger in group A than in group B (2.8 (1.6) mm2 v 1.8 (0.9) mm2; p = 0.007) and showed a positive linear relation with lesion and reference vessel size (r = 0.58 and 0.56, respectively; p < 0.001), but not with lumen narrowing. CONCLUSIONS The size of the emptied cavity inside ruptured plaques is on average larger in lesions with adaptive vascular remodelling, and shows a linear relation with lesion plaque and vessel size and with the reference dimensions, but not with the degree of lumen narrowing.