Jörg Herrmann

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P3 Lysophospholipid Receptor

Background— All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport–independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury. Methods and Results— In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by ≈20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL- and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P3 lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P3-deficient mice. Conclusions— Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/reperfusion injury in vivo via an S1P3-mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia.

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.

Prognostic implication of cardiac troponin T increase following stent implantation

Objective: To identify the incidence and clinical significance of myocardial injury following elective stent implantation. Design: Prospective clinical study with 278 consecutive patients undergoing stenting of de novo coronary or saphenous vein graft lesions. Incidence of periprocedural myocardial injury was assessed by analysis of 12 lead ECG, creatine kinase (CK; upper limit of normal (ULN) 70 IU/l for women, 80 IU/l for men), and cardiac troponin T (cTnT; point of care test; threshold 0.1 ng/ml) before and 6, 12, and 24 hours after the intervention. Major adverse cardiac events (MACE: acute myocardial infarction, bypass surgery, and cardiac death) were recorded during clinical follow up (mean (SD) 7.8 (5.3) months). Results: Following elective stenting, the rate of a positive cTnT status was 17.3%, the rate of CK increase of 1–3× ULN 14.7%, the rate of CK increase of > 3× ULN 1.4%, and the rate of Q wave myocardial infarction 0.4%. Cardiac mortality during follow up was higher in patients with postprocedurally increased CK (7.1% v 1.3%, p = 0.01, log rank) and cTnT (9.1% v 0.9%, p < 0.001, log rank). In addition, postprocedurally increased cTnT was associated with a higher overall incidence of MACE (13.1% v 4.0%, p < 0.01, log rank) and was identified as an independent factor for MACE during follow up (hazard ratio 3.27, 95% confidence interval 1.14 to 9.41, p = 0.028). Conclusions: Following elective stent implantation, a positive cTnT status identified patients at risk of a worse long term outcome. Treatment strategies have to be developed that lead to prognostic improvement by reducing periprocedural myocardial injury.

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.

High high-density lipoprotein-cholesterol reduces risk and extent of percutaneous coronary intervention-related myocardial infarction and improves long-term outcome in patients undergoing elective percutaneous coronary intervention

AIMS The study tested whether high-density lipoprotein-cholesterol (HDL-C) has an effect on percutaneous coronary intervention (PCI)-induced myocardial infarction and its prognosis. Elevation of cardiac troponin I (cTnI) > 3x upper normal limit after PCI is defined as PCI-related myocardial infarction (PMI) and is associated with a negative prognosis. No data exist on the relationship of HDL-C to PMI and PMI-related outcome. METHODS AND RESULTS Pre-procedural HDL-C levels and post-procedural peak cTnI levels were collected in 350 patients undergoing PCI. Data were analysed for PMI and for acute myocardial infarction (AMI) during follow-up. Patients with PMI (n = 115) had lower HDL-C levels than patients without PMI [n = 235; 1.17 mmol/L (0.75-2.51) vs. 1.27 mmol/L (0.70-2.87), P < 0.001]. Pre-procedural HDL-C levels were inversely related to the occurrence of PMI [odds ratio for PMI: 0.884, 95% CI: 0.80, 0.98; P = 0.02 for an HDL-C-increment of 5 mg/dL (0.13 mmol/L)] and to AMI during follow-up [hazard ratio (HR): 0.697, 95% CI: 0.54, 0.90; P = 0.005]. The occurrence of PMI was associated with an elevated HR for AMI (4.702, 95% CI: 1.79, 12.37; P = 0.002). Low-risk levels of pre-procedural HDL-C [men >or=40 mg/dL (>or=1.03 mmol/L), women >or=45 mg/dL (>or=1.16 mmol/L)] did not influence the negative effects of PMI on outcome (HR: 5.510, 95% CI: 1.43, 21.31; P = 0.013) and reduction of AMI-free survival [mean AMI-free survival time with PMI: 1167.5 days (95% CI: 1098.27, 1236.67) vs. 1240.7 days (95% CI: 1220.94, 1290.49) without PMI; log-rank P = 0.005]. Conclusion Small increases in HDL-C in patients undergoing elective PCI convert into a substantial reduction of risk for PMI, which has adverse effects on the long-term prognosis. Patients with PMI are at a high risk for AMI at any HDL-C level and therefore should receive particular monitoring by the treating physician over a long period after PCI.

Biochemische Marker bei ischämischen und nicht ischämischen Myokardschädigungen

ZusammenfassungHintergrund: Biochemische Marker sind seit fast 50 Jahren integrativer Bestandteil der nicht invasiven kardialen Diagnostik und haben mit den kardialen Troponinen angesichts ihres prognostischen Potentials bei akutem Koronarsyndrom eine Renaissance erfahren. Diagnostik: Nach den Empfehlungen der National Acadamy of Clinical Biochemistry und der International Federatuion of Clinical Chemistry stellen das kardiale Troponin T und das kardiale Troponin I den neuen Goldstandard in der biochemischen kardialen Ischämiediagnostik dar. Charakteristikum dieser neuen Marker ist zum einen das verbesserte diagnostische Potential, das sich in der Wahl zweier Grenzwerte zur Differenzierung einer minimalen Myokardschädigung vom definitiven akuten Myokardinfarkt widerspiegelt. Zum anderen erlauben die neuen kardiospezifischen Marker eine Risikostratifizierung in dem klinisch bedeutsamen Szenario des akuten Koronarsyndroms (zwei- bis dreifach erhöhte Mortalitätsrate für Patienten mit ST-Strecken-Hebung oder Ruhe-Angina pectoris und kardialer Troponinerhöhung zum Zeitpunkt der Aufnahme). Eine weitere Indikation für die Bestimmung karidaler Marker liegt in der Beurteilung des Therapieerfolgs invasiver und nicht invasiver Reperfusionsstrategien und in der nicht invasiven Diagnostik von nicht ischämischen Myokardschädigungen (Myokarditis, Herzkontusion und Chemotherapie). Schlussfolgerung: Biochemische kardiale Marker sind zur Diagnostik ischämischer und nicht ischämischer Myokardschädigungen einsetzbar. Die kardialen Troponine scheinen sich dabei als Goldstandard für das neue Millennium zu etablieren.AbstractBackground: Biochemical markers have been an integrative part of non-invasive diagnostic strategies in cardiology for nearly 50 years, experiencing a renascence by the recently acknowledged prognostic potential of cardiac troponins in acute coronary syndromes. Diagnosis: According to the guidelines of the National Academy of Clinical Biochemistry and the International Federation of Clinical Chemistry cardiac troponin T and cardiac troponin I should be considered as the new “gold markers” of ischemic myocardial injury. One characteristic feature of these new markers is the improved diagnostic potential, reflected by the choice of two cut-off values to distinguish minor myocardial injury from acute myocardial infarction. In addition, cardiac troponins allow risk stratification in the clinical setting of acute coronary syndromes: approximately threefold higher mortaligy rate for patients with rest angina or ST segment elevation and cardiac troponin elevation on admission. Other indications for cardiac marker analysis are monitoring of therapeutic success in case of invasive and non-invasive reperfusion strategies and non-invasive diagnosis of non-ischemic myocardial injury (myocarditis, cardiac contusion and chemotherapy). Conclusion: Biochemical cardiac markers are a useful tool in the diagnosis of both ischemic and non-ischemic myocardial injury. Among these, cardiac troponins seem to become the gold markers for the new millennium.

Preintervention arterial remodeling affects vessel stretch and plaque extrusion during coronary stent deployment as demonstrated by three-dimensional intravascular ultrasound

The mechanisms of lumen enlargement during stent implantation may be significantly affected by arterial remodeling. To assess effects of lesion remodeling, we performed 3-dimensional intravascular ultrasound (IVUS) analyses in 55 coronary lesions before and after deployment of balloon-expandable stents. Standard quantitative analysis was performed, and arterial remodeling was assessed by the remodeling index (target site divided by mean of proximal and distal reference segment vessel areas), which classified lesions into group A (remodeling index < or =1, negative or intermediate remodeling, n = 40) or group B (remodeling index >1, positive remodeling, n = 15) lesions. Characteristics of the 55 patients and the interventional procedures were similar in the 2 groups. IVUS demonstrated that stenting resulted in increased lumen and vessel dimensions and in a reduced plaque size (p < or =0.001 each) in both group A and group B lesions. The extent of lumen increase inside the stents was almost identical, but resulted from different mechanisms: (1) vessel stretch was greater in group A (p <0.002 at minimum lumen site); (2) plaque compression (or embolization) tended to be greater in group B (p = 0.05, along entire stented segment); (3) plaque redistribution within the stent was observed in both groups (p <0.005 both); and (4) significant (p <0.01) plaque extrusion into the distal reference segment was found in group B only. Thus, the remodeling pattern of coronary lesions has a significant impact on the mechanisms of lumen enlargement during stent deployment. Lesions with positive remodeling show more plaque extrusion into the distal reference and less stent-induced vessel stretch than those with negative remodeling.

Can right-sided atrioventricular sequential pacing provide benefit for selected patients with severe congestive heart failure?

This study reports on the methods and results of applying right-sided atrioventricular (AV) pacing in 26 patients with advanced cardiomyopathy. Ten of these patients had ischemic cardiomyopathy. Of the 16 patients with nonischemic cardiomyopathy, 10 were idiopathic and 6 were due to secondary causes. The patients had a mean age of 56 +/- 12 years and a left ventricular ejection fraction of 26 +/- 11%. Two transvenous stimulation electrodes were temporarily placed in the high right atrium and right ventricle, respectively. A Swan Ganz catheter was positioned into the pulmonary artery to determine cardiac output by the thermodilution method and to measure the pressure in the pulmonary artery and right atrium. In addition, aortic pressure was measured through a catheter sheath via the right femoral artery. Systemic and pulmonary vascular resistance were calculated. Stimulation was performed in VVI and DDD pacing modes using different AV intervals (40, 80, 125, 150, 175, 200, and 250 msec). No increase of cardiac output was observed for the overall study cohort (p = 0.51). At VVI pacing, stroke volume significantly decreased from 66 +/- 20 mL to 53 +/- 13 mL (p < 0.01). We distinguished between responders who developed an increase of cardiac output of > 1 L/min (n = 12, 46%) and nonresponders (n = 14, 54%). Etiology of either ischemic or nonischemic cardiomyopathy for responders, as well as conduction disturbances (first-degree AV block, LBBB, RBBB), were equally distributed among both groups. Using an AV delay of 150 and 175 msec, responders to DDD pacing derived a significant increase in cardiac output. An AV delay of 150 msec produced both a significant increase of stroke volume and decrease of systemic vascular resistance. In 46% of patients with dilated cardiomyopathy of either ischemic or nonischemic origin, right-sided AV-sequential pacing brought about an improvement of left ventricular function in terms of enhanced cardiac output. We suggest individual testing in all patients with severe left ventricular dysfunction to find responders.

Dose-dependent effects of intracoronary verapamil on systemic and coronary hemodynamics

Calcium antagonists are used in interventional cardiology to prevent coronary vasoconstriction or to overcome the no-reflow phenomenon. The aim of the current study was to evaluate the dose-dependent effects of intracoronary verapamil on systemic and coronary hemodynamics. In 20 patients scheduled for routine coronary angiography, heart rate, blood pressure, and ECG recordings were recorded continuously and intracoronary flow velocity was obtained by intracoronary Doppler measurements in angiographically normal vessels. The cross-sectional area, measured by quantitative coronary angiography, allowed the calculation of coronary blood flow (CBF) and the coronary vascular resistance index (CVRI). Without premedication, increasing dosages of verapamil (0.01 mg, 0.1 mg, 1.0 mg, and 2.0 mg) were injected into the left coronary artery. Intracoronary verapamil administration led to a decrease in systemic blood pressure only after administration of 1.0 mg or 2.0 mg (change in mean arterial pressure: from 87.6 ± 14.6 mmHg to 80.1 ± 14.9 mmHg and 78.5 ± 13.9 mmHg, respectively; both P < 0.05) without a change in heart rate. Epicardial diameters of the left coronary artery increased only at dosages of 1.0 mg and 2.0 mg (from 2.14 ± 0.4 mm to 2.22 ± 0.3 mm, P < 0.01), whereas the coronary blood flow velocity increased significantly at the smallest dosage of 0.01 mg (from 19.9 ± 8.7 cm/s to 33.2 ± 14.9 cm/s, P < 0.001) and was further enhanced with increasing dosages. CBF increased and CVRI decreased at every dosage of verapamil compared with baseline values. CBF increased also after 0.1 mg (from 13.5 ± 6.5 mL/min to 19.5 ± 9.3 mL/min; P < 0.05), reaching a maximal effect after administration of 1.0 mg verapamil (26.3 ± 16.1 mL/min, P < 0.05). Application of 2.0 mg did not further increase CBF compared with 1.0 mg. Intracoronary application of verapamil leads to a decrease in systemic blood pressure at higher dosages, whereas heart rate remains unchanged at any dosage. The maximal increase in coronary blood flow and decrease in vascular resistance can be reached by administration of 1.0 mg verapamil into the left coronary artery.

Chest pain after coronary interventional procedures. Incidence and pathophysiology.

Chest pain following successful percutaneous coronary interventions is a common problem. Although the development of chest pain after coronary interventions may be of benign character, it is disturbing to patients, relatives and hospital staff. Such pain may be indicative of acute coronary artery closure, coronary artery spasm or myocardial infarction, but may also simply reflect local coronary artery trauma. The distinction between these causes of chest pain is crucial in selecting optimal care. Management of these patients may involve repeat coronary angiography and additional intervention. Commonly, repeat coronary angiography following percutaneous transluminal coronary angioplasty (PTCA) in patients with chest pain demonstrates widely patent lesion sites suggesting that the pain was due to coronary artery spasm, coronary arterial wall stretching or was of non-cardiac origin. As reported by the National Heart, Lung and Blood Institute PTCA Registry, 4.6% of patients after angioplasty have coronary occlusions, 4.8% suffer a myocardial infarction, and 4.2% have coronary spasm. The frequency of chest pain after new device coronary interventions (atherectomy and stenting) seems to be even higher. However, only the minority of patients with post-procedural chest pain have indeed an ischemic event. Therefore, the vast majority of patients have recurrent chest pain without any signs of ischemia. There is some evidence that non-ischemic chest pain after coronary interventions is more common after stent implantation as compared to PTCA (41% vs. 12%). This may be due to the continuous stretching of the arterial wall by the stent as the elastic recoil occurring after PTCA is minimized. In conclusion, chest pain after coronary interventional procedures may potentially be hazardous when due to myocardial ischemia. However, especially after coronary stent placement, cardiologists must consider “stretch pain” due to the overdilation and stretching of the artery caused by the stent in the differential diagnosis. Clinically, it is, therefore, important to recognize that in addition to ischemia-related chest pain other types of chest pain do exist with cardiac origin.ZusammenfassungAngina pectoris nach erfolgreicher koronarer Intervention ist ein häufig vorkommendes Problem. Auch wenn die Entwicklung von Angina pectoris nach einem interventionellen Eingriff von benignem Charakter sein kann, ist sie beängstigend für die Patienten, die Angehörigen und das medizinische Personal. Brustschmerz kann ein Anzeichen sein für einen akuten Verschluß des Gefäßes, einen Spasmus der Koronararterie oder einen Myokardinfarkt; er kann aber auch durch ein lokales Trauma bedingt sein. Die Unterscheidung dieser Ursachen ist von großer Bedeutung für die Wahl der optimalen Therapie. Diese beinhaltet wiederholte koronare Angiographie und, wenn nötig, eine erneute Intervention. Häufig sieht man jedoch bei wiederholter Angiographie nach PTCA ein weit offenes Gefäß. In diesen Fällen ist die Ursache der Schmerzsymptomatik am ehesten auf einen bereits gelösten Koronararterienspasmus. Schmerzrezeptoren in der Gefäßwand oder nichtkardiale Genese zurückzuführen. Ein Bericht der „National Heart, Lung and Blood Institute PTCA Registry” zeigte, daß 4,6% der Patienten nach Angioplastie einen koronaren Verschluß haben 4,8% erleiden einen Myokardinfarkt, und 4,2% haben einen Koronarspasmus. Die Inzidenz von Brustschmerz nach koronarer Atherektomie und Stent-Implantation erscheint sogar noch höher. Eine Minderheit der Patienten mit post-interventionellem Brustschmerz erleidet jedoch nur ein ischämisches Ereignis. Die Mehrheit der Patienten leidet demnach an Brustschmerzen ohne ein schämisches Korrelat. Es gibt Hinweise darauf, daß der nichtischämische Brustschmerz nach koronarer Intervention häufiger nach Stent-Implantation auftritt als nach PTCA (41% vs. 12%). Das liegt möglicherweise an der Überdehnung des Gefäßes durch den Stent, da die elastischen Rückstellkräfte im Gegensatz zur PTCA blockiert werden.Zusammenfassend läßt sich sagen, daß ein Brustschmerz nach koronarer Intervention ischämisch bedingt sein kann. Besonders nach koronarer Stent-Implantation muß jedoch auch der „Dehnungsschmerz” bedingt durch eine Überdehnung des Gefäßes durch den Stent, in der Differentialdiagnose berücksichtigt werden.